Language：English   Publishing type：Research paper (scientific journal)  

The excitatory glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) contribute to epileptogenesis. Thirty patients with epilepsy and 31 healthy controls are scanned using positron emission tomography with our recently developed radiotracer for AMPARs, [11C]K-2, which measures the density of cell-surface AMPARs. In patients with focal-onset seizures, an increase in AMPAR trafficking augments the amplitude of abnormal gamma activity detected by electroencephalography. In contrast, patients with generalized-onset seizures exhibit a decrease in AMPARs coupled with increased amplitude of abnormal gamma activity. Patients with epilepsy had reduced AMPAR levels compared with healthy controls, and AMPARs are reduced in larger areas of the cortex in patients with generalized-onset seizures compared with those with focal-onset seizures. Thus, epileptic brain function can be regulated by the enhanced trafficking of AMPAR due to Hebbian plasticity with increased simultaneous neuronal firing and compensational downregulation of cell-surface AMPARs by the synaptic scaling.

DOI： 10.1016/j.xcrm.2023.101020

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Introduction: AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor) receptors play a central role in neurotransmission and neuronal function. A positron emission tomography (PET) tracer for AMPA re-ceptors, [C-11]K-2, was recently developed by us to visualize AMPA receptors in the living human brain. [C-11]K-2 is a derivative of 4-[2-(phenylsulphonylamino)ethylthio]-2,6-difuluoro-phenoxyacetamide (PEPA), and is labeled with the radioactive isotope C-11, which has a short half-life. PET drugs are usually labeled with F-18 because of its long half-life. Therefore, we screened and identified potential F-18-labeled PET drugs for AMPA receptors (AMPA-PET drugs), which could provide an image equivalent to that of [C-11]K-2. Methods: Derivatives of K-2 labeled with F-18 were synthesized and administered to rats and PET imaging was performed. The transferability of each compound to the brain and its correlation with the PET image of [C-11]K-2 were evaluated from the obtained PET images. Furthermore, the specific binding ability of promising compounds to the AMPA receptor was evaluated by the PET imaging of rats, which we specifically knocked down the expression of AMPA by the lentivirus-mediated introduction of short hairpin RNA (shRNA) targeted to subunits of the AMPA receptor (GluA1-A3). The specific binding ability was also evaluated through electrophysiological experiments with acute brain slices. Results: Some of the synthesized F-18-labeled candidate compounds showed a distribution similar to that of K-2, with reasonable transferability to the brain. In addition, from the evaluation of the specific binding ability to the AMPA receptor, a promising structure of an 18F-labeled AMPA PET drug was identified. This study also revealed that the alkylation of the sulfonamide group of PEPA enhances brain transferability.

DOI： 10.1016/j.nucmedbio.2022.04.009

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Presurgical identification of the epileptogenic zone is a critical determinant of seizure control following surgical resection in epilepsy. Excitatory glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor is a major component of neurotransmission. Although elevated α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor levels are observed in surgically resected brain areas of patients with epilepsy, it remains unclear whether increased α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor-mediated currents initiate epileptic discharges. We have recently developed the first PET tracer for α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor, [11C]K-2, to visualize and quantify the density of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors in living human brains. Here, we detected elevated [11C]K-2 uptake in the epileptogenic temporal lobe of patients with mesial temporal lobe epilepsy. Brain areas with high [11C]K-2 uptake are closely colocalized with the location of equivalent current dipoles estimated by magnetoencephalography or with seizure onset zones detected by intracranial electroencephalogram. These results suggest that epileptic discharges initiate from brain areas with increased α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors, providing a biological basis for epileptic discharges and an additional non-invasive option to identify the epileptogenic zone in patients with mesial temporal lobe epilepsy.

DOI： 10.1093/braincomms/fcac023

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The glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) is an important molecule in neurotransmission. We have recently developed the first positron emission tomography (PET) tracer [11C]K-2 to visualize and quantify AMPARs in the living human brain. After injection, [11C]K-2 is hydrolyzed at the terminal amide (and is thus metabolized to a major metabolite, [11C]K-2OH) within 10 min, representing the PET image in rodents and humans. Here, we found that K-2OH did not penetrate the cell membrane but slowly passed through the blood brain barrier (BBB) with paracellular transport. Furthermore, major efflux transporters in the BBB did not carry K-2OH. Logan graphical analysis exhibited reversible binding kinetics of this radiotracer in healthy individuals; these results demonstrated that the PET image of this tracer represents cell surface AMPARs with passive penetration of [11C]K-2OH through the BBB, resulting in reversible binding kinetics. Thus, PET images with this tracer depict the physiologically crucial fraction of AMPARs.

DOI： 10.1016/j.neures.2021.05.009

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

[11C]K-2, a radiotracer exhibiting high affinity and selectivity for α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs), is suitable for the quantification of AMPARs in living human brains and potentially useful in the identification of epileptogenic foci in patients. This study aimed to estimate the radiation doses of [11C]K-2 in various organs and calculate the effective dose after injection of [11C]K-2 in healthy human subjects. Twelve healthy male subjects were registered and divided into two groups (370 or 555 MBq of [11C]K-2), followed by 2 h whole-body scans. We estimated the radiation dose of each organ and then calculated the effective dose for each subject. The highest uptake of [11C]K-2 was observed in the liver, while the brain also showed relatively high uptake. The urinary bladder exhibited the highest radiation dose. The kidneys and liver also showed high radiation doses after [11C]K-2 injections. The effective dose of [11C]K-2 ranged from 5.0 to 5.2 μSv/MBq. Our findings suggest that [11C]K-2 is safe in terms of the radiation dose and adverse effects. The injection of 370-555 MBq (10 to 15 mCi) for PET studies using this radiotracer is applicable in healthy human subjects and enables serial PET scans in a single subject.

DOI： 10.1038/s41598-021-81002-3

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Other Link： http://www.nature.com/articles/s41598-021-81002-3

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Although aberrations in the number and function of glutamate AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors are thought to underlie neuropsychiatric disorders, no methods are currently available for visualizing AMPA receptors in the living human brain. Here we developed a positron emission tomography (PET) tracer for AMPA receptors. A derivative of 4-[2-(phenylsulfonylamino)ethylthio]-2,6-difluoro-phenoxyacetamide radiolabeled with 11C ([11C]K-2) showed specific binding to AMPA receptors. Our clinical trial with healthy human participants confirmed reversible binding of [11C]K-2 in the brain according to Logan graphical analysis (UMIN000020975; study design: non-randomized, single arm; primary outcome: dynamics and distribution volumes of [11C]K-2 in the brain; secondary outcome: adverse events of [11C]K-2 during the 4-10 d following dosing; this trial met prespecified endpoints). In an exploratory clinical study including patients with epilepsy, we detected increased [11C]K-2 uptake in the epileptogenic focus of patients with mesial temporal lobe epilepsy, which was closely correlated with the local AMPA receptor protein distribution in surgical specimens from the same individuals (UMIN000025090; study design: non-randomized, single arm; primary outcome: correlation between [11C]K-2 uptake measured with PET before surgery and AMPA receptor protein density examined by biochemical study after surgery; secondary outcome: adverse events during the 7 d following PET scan; this trial met prespecified endpoints). Thus, [11C]K-2 is a potent PET tracer for AMPA receptors, potentially providing a tool to examine the involvement of AMPA receptors in neuropsychiatric disorders.

DOI： 10.1038/s41591-019-0723-9

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Association for the Advancement of Science  

Brain damage such as stroke is a devastating neurological condition that may severely compromise patient quality of life. No effective medication-mediated intervention to accelerate rehabilitation has been established. We found that a small compound, edonerpic maleate, facilitated experience-driven synaptic glutamate AMPA (a-amino-3hydroxy-5-methyl-4-isoxazole-propionic-acid) receptor delivery and resulted in the acceleration of motor function recovery after motor cortex cryoinjury in mice in a training-dependent manner through cortical reorganization. Edonerpic bound to collapsin-response-mediator-protein 2 (CRMP2) and failed to augment recovery in CRMP2-deficient mice. Edonerpic maleate enhanced motor function recovery from internal capsule hemorrhage in nonhuman primates. Thus, edonerpic maleate, a neural plasticity enhancer, could be a clinically potent small compound with which to accelerate rehabilitation after brain damage.

DOI： 10.1126/science.aao2300

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

While spinal cord injury (SCI) aggravates the quality of life in humans by severe paralysis, clinical intervention to promote functional recovery from SCI is limited. We recently identified a small compound, edonerpic maleate (edonerpic MA), which accelerates training-dependent motor functional recovery from brain damage in rodents (cryo-genic cortical injury) and non-human primates (internal capsule haemorrhage) by the facilitation of experience-dependent synaptic trafficking of glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. In the present study, we investigated whether edonerpic MA accelerates functional recovery after SCI in non-human primates. Six adult monkeys (Macaca fuscata) received a unilateral SCI between the C6 and C7 segment. After the SCI, upper limb motor function was immediately impaired and the animals were assigned to receive vehicle (n = 3) or 3 mg/kg/day edonerpic maleate (n = 3) by intramuscular injection for 2 months. The rehabilitative training and evaluation of behaviour using the slit task were performed 5 days a week for 2 months after SCI. The edonerpic MA-treated group showed significantly improved grasping movements than the control group. After recovery reached a plateau, we examined the somatotopic map of the contralesional primary motor cortex (M1) using intracortical microstimulation. The motor representation of wrist territory at contralesional M1 was larger in the edonerpic MA-treated group than in the control group. We concluded that edonerpic MA accelerates the recovery of grasping movements after SCI, accompanied by cortical somatotopic reorganization. Since edonerpic MA enhances recovery from damage in the central nervous system at multiple levels, treatment with edonerpic MA combined with rehabilitative training may represent a novel therapy for not only stroke but also for SCI. Uramaru et al. revealed the efficacy of edonerpic maleate on grasping movement after cervical spinal cord injury and the change of cortical motor representation with intracortical microstimulation in non-human primates. They proposed that edonerpic maleate could be a therapeutic alternative for paralysis after spinal cord injury.See Machado and Hollis (https://doi.org/10.1093/braincomms/fcaf076) for a scientific commentary on this article.

DOI： 10.1093/braincomms/fcaf036

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Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

Functional recovery from brain damage, such as stroke, is a plastic process in the brain. The excitatory glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) plays a crucial role in neuronal functions, and the synaptic trafficking of AMPAR is a fundamental mechanism underlying synaptic plasticity. We recently identified a collapsin response mediator protein 2 (CRMP2)-binding compound, edonerpic maleate, which augments rehabilitative training-dependent functional recovery from brain damage by facilitating experience-driven synaptic delivery of AMPARs. In animals recovering from cryogenic brain injury, a potential compensatory area adjacent to the injured region was observed, where the injection of CNQX, an AMPAR antagonist, significantly attenuated functional recovery. In the compensatory brain area of animals recovering from cryogenic injury, the administration of edonerpic maleate enhanced both excitatory and inhibitory synaptic inputs at pyramidal neurons. In contrast, recovered animals that did not receive the drug exhibited augmentation of only excitatory synaptic input. The threshold of picrotoxin-induced epileptic seizure in recovered animals without edonerpic maleate treatment was lower than in intact animals and recovered animals with edonerpic maleate. Thus, edonerpic maleate enhances motor function recovery from brain damage by balancing excitatory and inhibitory synaptic inputs, which helps prevent epileptic seizures during recovery.

DOI： 10.3389/fncir.2024.1492043

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BACKGROUND: While altered expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) type receptor has been reported in postmortem studies of schizophrenia, these findings are inconsistent. Therefore, we aimed to systematically review postmortem studies that investigated AMPA receptor expressions in schizophrenia. METHODS: A systematic literature search was conducted for postmortem studies that measured AMPA receptor subunit expressions or receptor bindings in schizophrenia compared to healthy individuals on February 3, 2021, using Medline and Embase. RESULTS: A total of 39 relevant articles were identified from 1360 initial reports. The dorsolateral prefrontal cortex (DLPFC) was the most investigated region (15 studies), followed by the medial temporal lobe (8 studies). For the DLPFC, 4/15 studies (26.7%) showed increased AMPA receptor binding or subunit expression in patients with schizophrenia compared to that in controls, especially in GRIA1 and GRIA4, 2/15 studies (13.3%) reported a decrease, particularly in GRIA2, and 8/15 studies (56.7%) found no significant differences. A decreased expression or receptor binding was observed in 6/8 studies (75.0%) in the subregions of the hippocampus in patients with schizophrenia compared to that in controls, whereas the other two studies found no significant differences. CONCLUSION: Published data have reported decreased subunit expression or receptor binding in the hippocampus in schizophrenia. These findings were inconsistent in other brain regions, which might be due to the heterogeneity of this population, various study design, physiological changes after death, and limited number of studies. Future in vivo studies are warranted to examine AMPA receptor expressions in human brains, together with their comprehensive clinical characterization.

DOI： 10.1016/j.schres.2022.02.033

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Collapsin response mediator proteins (CRMPs) have been identified as mediating proteins of repulsive axon guidance cue Semaphorin-3A (Sema3A). Phosphorylation of CRMPs plays a crucial role in the Sema3A signaling cascade. It has been shown that Fyn phosphorylates CRMP1 at Tyrosine 504 residue (Tyr504); however, the physiological role of this phosphorylation has not been examined. We found that CRMP1 was the most strongly phosphorylated by Fyn among the five members of CRMPs. We confirmed Tyr504 phosphorylation of CRMP1 by Fyn. Immunocytochemistry of mouse dorsal root ganglion (DRG) neurons showed that phosphotyrosine signal in the growth cones was transiently increased in the growth cones upon Sema3A stimulation. Tyr504-phosphorylated CRMP1 also tended to increase after Sema3A simulation. Ectopic expression of a single amino acid mutant of CRMP1 replacing Tyr504 with phenylalanine (CRMP1-Tyr504Phe) suppressed Sema3A-induced growth cone collapse response in chick DRG neurons. CRMP1-Tyr504Phe expression in mouse hippocampal neurons also suppressed Sema3A but not Sema3F-induced growth cone collapse response. Immunohistochemistry showed that Tyr504-phosphorylated CRMP1 was present in the cell bodies and in the dendritic processes of mouse cortical neurons. CRMP1-Tyr504Phe suppressed Sema3A-induced dendritic growth of primary cultured mouse cortical neurons as well as the dendritic development of cortical pyramidal neurons in vivo. Fyn± ; Crmp1± double heterozygous mutant mice exhibited poor development of cortical layer V basal dendrites, which was the similar phenotype observed in Sema3a-/- , Fyn-/- , and Crmp1-/- mice. These findings demonstrate that Tyr504 phosphorylation of CRMP1 by Fyn is an essential step of Sema3A-regulated dendritic development of cortical pyramidal neurons. (247 words).

DOI： 10.1111/jnc.15304

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The semaphorin family is a well-characterized family of secreted or membrane-bound proteins that are involved in activity-independent neurodevelopmental processes, such as axon guidance, cell migration, and immune functions. Although semaphorins have recently been demonstrated to regulate activity-dependent synaptic scaling, their roles in Hebbian synaptic plasticity as well as learning and memory remain poorly understood. Here, using a rodent model, we found that an inhibitory avoidance task, a hippocampus-dependent contextual learning paradigm, increased secretion of semaphorin 3A in the hippocampus. Furthermore, the secreted semaphorin 3A in the hippocampus mediated contextual memory formation likely by driving AMPA receptors into hippocampal synapses via the neuropilin1-plexin A4-semaphorin receptor complex. This signaling process involves alteration of the phosphorylation status of collapsin response mediator protein 2, which has been characterized as a downstream molecule in semaphorin signaling. These findings implicate semaphorin family as a regulator of Hebbian synaptic plasticity and learning.

DOI： 10.1111/ejn.15210

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Publishing type：Research paper (scientific journal)   Publisher：Japan Academy  

Psychiatric and neurological disorders severely hamper patient's quality of life. Despite their high unmet needs, the development of diagnostics and therapeutics has only made slow progress. This is due to limited evidence on the biological basis of these disorders in humans. Synapses are essential structural units of neurotransmission, and neuropsychiatric disorders are considered as "synapse diseases". Thus, a translational approach with synaptic physiology is crucial to tackle these disorders. Among a variety of synapses, excitatory glutamatergic synapses play central roles in neuronal functions. The glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) is a principal component of glutamatergic neurotransmission; therefore, it is considered to be a promising translational target. Here, we review the limitations of current diagnostics and therapeutics of neuropsychiatric disorders and advocate the urgent need for the promotion of translational medicine based on the synaptic physiology of AMPAR. Furthermore, we introduce our recent translational approach to these disorders by targeting at AMPARs.

DOI： 10.2183/pjab.97.001

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Language：Japanese   Publisher：(株)ニュー・サイエンス社  

根本的治療法が存在しない神経疾患では機能障害の後遺は避け難い。機能障害を改善・代償するには疾患の進行や再発を抑制する治療に加えて、リハビリテーションが重要である。近年、脳卒中に限らず、脊髄小脳変性症、パーキンソン病、多発性硬化症といった慢性進行性疾患でもリハビリテーション法の改良が試みられている。脳神経科学ではリハビリテーションによる機能回復は非障害脳領域における機能的再構築に依拠するとされてきたが、ヒト生体脳において疾患毎の機能回復能の神経生理学的理解は不十分である。我々は、急性脳損傷モデルにおいて、グルタミン酸AMPA受容体のシナプス後膜への移行促進がリハビリテーションによる運動機能回復を促進することを薬理学的に示した。現在はこの研究に動機づけられ、PET画像で得られるAMPA受容体発現密度分布を手掛かりとして、リハビリテーションを可能とする「機能回復ネットワーク」の疾患横断的解明に取り組んでいる。(著者抄録)

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PURPOSE OF REVIEW: Stroke is a devastating illness which severely attenuates quality of life because of paralysis. Despite recent advances in therapies during acute phase such as thrombolytic therapy, clinical option to intervene the process of rehabilitation is limited. No pharmacological intervention that could enhance the effect of rehabilitation has not been established. Recent articles, which are summarized in the review article, reported novel small compound which accelerates training-dependent motor function recovery after brain damage. RECENT FINDINGS: A novel small compound, edonerpic maleate, binds to collapsin response mediator protein 2 (CRMP2) and enhance synaptic plasticity leading to the acceleration of rehabilitative training-dependent functional recovery after brain damage in rodent and nonhuman primate. The clinical trial to test this effect in human is now ongoing. Future preclinical and clinical studies will delineate the potentials of this compound. SUMMARY: A novel CRMP2-binding small compound, edonerpic maleate, accelerates motor function recovery after brain damage in rodent and nonhuman primate.

DOI： 10.1097/WCO.0000000000000748

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DOI： 10.1161/STROKEAHA.119.023720

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Neuropsychopharmacology Reports  

BACKGROUND AND OBJECTIVES: Altered trafficking of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors has been reported in postmortem studies and suggested the involvement of AMPA receptors in the pathophysiology underpinning addictive disorders. However, these findings seemed mixed. METHODS: A systematic literature search was conducted, using PubMed and Embase (last search, August 2018), to identify human postmortem studies that examined the expression of proteins and mRNA of AMPA receptor subunits in patients with addictive disorders in comparison with healthy controls. RESULTS: Twelve (18 studies) out of 954 articles were identified to be relevant. Eight studies included alcohol use disorders, and four studies included heroin/cocaine abusers. The most frequently investigated regions were the hippocampus (three studies), amygdala (three studies), and putamen (three studies). In summary, two out of the three studies showed an increase in the expression of AMPA receptors in the hippocampus, while the other study found no change. Two studies to examine the amygdala demonstrated either a decreased or no change in receptor expression or binding. Concerning putamen, two studies showed no significant change whereas an overexpression of receptors was observed in the other. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: The hippocampus and amygdala may be pertinent to addictive disorders through their functions on learning and memory, whereas findings in other regions were inconsistent across the studies. Human postmortem studies are prone to degenerative changes after death. Moreover, only qualitative assessment was conducted because of the limited, heterogenous data. These limitations emphasize the need to investigate AMPA receptors in the living human brains.

DOI： 10.1002/npr2.12058

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AIM: While emotional processing is implicated in various psychiatric illnesses, its differences among diagnoses are unclear. We compared associative learning of social values in patients with depression and schizophrenia by measuring skin conductance response to interpersonal stimuli. METHODS: We included 20 female outpatients each with depression and schizophrenia. They underwent Pavlovian conditioning experiments in response to a classical aversive sound, and an interpersonal stimulus that was designed to cause aversive social conditioning with actors' faces coupled with negative verbal messages. Multiple regression analysis was performed to examine the associations between the degree of conditioned response and the clinical characteristics of the participants. RESULTS: Conditioned responses during the acquisition phase in both conditions were higher in depression compared to schizophrenia. Patients with depression successfully showed fear conditioning in both conditions, and they exhibited slower extinction in the interpersonal condition. The conditioned response during the extinction phase showed a positive association with Emotion Regulation Questionnaire Expressive Suppression score, and a negative association with the Emotion Regulation Questionnaire Cognitive Reappraisal score and the use of antidepressants. Patients with schizophrenia did not become conditioned in either of the conditions. The Positive and Negative Syndrome Scale Negative Syndrome score was negatively associated with the degree of conditioned response during the acquisition phase in the interpersonal condition. CONCLUSION: Female patients with schizophrenia, especially those who prominently demonstrated negative symptoms, suggested their intrinsic impairments in the associative learning of social context. Antidepressants and adaptive emotional regulation strategy may enhance the extinction learning of aversive social conditioning in depression.

DOI： 10.1111/pcn.12805

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Throughout life, individuals learn to predict a punishment via its association with sensory stimuli. This process ultimately prompts goal-directed actions to prevent the danger, a behavior defined as avoidance. Neurons in the lateral habenula (LHb) respond to aversive events as well as to environmental cues predicting them, supporting LHb contribution to cue-punishment association. However, whether synaptic adaptations at discrete habenular circuits underlie such associative learning to instruct avoidance remains elusive. Here, we find that, in mice, contingent association of an auditory cue (tone) with a punishment (foot shock) progressively causes cue-driven LHb neuronal excitation during avoidance learning. This process is concomitant with the strengthening of LHb AMPA receptor-mediated neurotransmission. Such a phenomenon occludes long-term potentiation and occurs specifically at hypothalamus-to-habenula synapses. Silencing hypothalamic-to-habenulainputs or optically inactivating postsynaptic AMPA receptors within the LHb disrupts avoidance learning. Altogether, synaptic strengthening at a discrete habenular circuit transforms neutral stimuli into salient punishment-predictive cues to guide avoidance.

DOI： 10.1016/j.neuron.2019.01.025

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Exposure to a stressful environment early in life can cause psychiatric disorders by disrupting circuit formation. Actin plays central roles in regulating neuronal structure and protein trafficking. We have recently reported that neonatal isolation inactivated ADF/cofilin, the actin depolymerizing factor, resulted in a reduced actin dynamics at spines and an attenuation of synaptic alpha-amino-3-hydroxy-5-methyl-4- isoxazole propionic acid (AMPA) receptor delivery in the juvenile rat medial prefrontal cortex (mPFC), leading to altered social behaviours. Here, we investigated the impact of neonatal social isolation in the developing rat barrel cortex. Similar to the mPFC study, we detected an increase in stable actin fraction in spines and this resulted in a decreased synaptic AMPA receptor delivery. Thus, we conclude that early life social isolation affects multiple cortical areas with common molecular changes.

DOI： 10.1038/s41598-017-08849-3

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

The synaptic delivery of neurotransmitter receptors, such as GluA1 AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors, mediates important processes in cognitive function, including memory acquisition and retention. Understanding the roles of these receptors has been hampered by the lack of a method to inactivate them in vivo with high spatiotemporal precision. We developed a technique to inactivate synaptic GIuA1 AMPA receptors in vivo using chromophore-assisted light inactivation (CALI). We raised a monoclonal antibody specific for the extracellular domain of GluA1 that induced effective CALI when conjugated with a photosensitizer (eosin). Mice that had been injected in the CA1 hippocampal region with the antibody conjugate underwent a fear memory task. Exposing the hippocampus to green light using an implanted cannula erased acquired fear memory in the animals by inactivation of synaptic GluA1. Our optical technique for inactivating synaptic proteins will enable elucidation of their physiological roles in cognition.

DOI： 10.1038/nbt.3710

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATL ACAD SCIENCES  

Social separation early in life can lead to the development of impaired interpersonal relationships and profound social disorders. However, the underlying cellular and molecular mechanisms involved are largely unknown. Here, we found that isolation of neonatal rats induced glucocorticoid-dependent social dominance over nonisolated control rats in juveniles from the same litter. Furthermore, neonatal isolation inactivated the actin-depolymerizing factor (ADF)/cofilin in the juvenile medial prefrontal cortex (mPFC). Isolation-induced inactivation of ADF/cofilin increased stable actin fractions at dendritic spines in the juvenile mPFC, decreasing glutamate synaptic AMPA receptors. Expression of constitutively active ADF/cofilin in the mPFC rescued the effect of isolation on social dominance. Thus, neonatal isolation affects spines in the mPFC by reducing actin dynamics, leading to altered social behavior later in life.

DOI： 10.1073/pnas.1606351113

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Patient-specific induced pluripotent stem cells (iPSCs) facilitate understanding of the etiology of diseases, discovery of new drugs and development of novel therapeutic interventions. A frequently used starting source of cells for generating iPSCs has been dermal fibroblasts (DFs) isolated from skin biopsies. However, there are also numerous repositories containing lymphoblastoid B-cell lines (LCLs) generated from a variety of patients. To date, this rich bioresource of LCLs has been underused for generating iPSCs, and its use would greatly expand the range of targeted diseases that could be studied by using patient-specific iPSCs. However, it remains unclear whether patient's LCL-derived iPSCs (LiPSCs) can function as a disease model. Therefore, we generated Parkinson's disease patient-specific LiPSCs and evaluated their utility as tools for modeling neurological diseases. We established iPSCs from two LCL clones, which were derived from a healthy donor and a patient carrying PARK2 mutations, by using existing non-integrating episomal protocols. Whole genome sequencing (WGS) and comparative genomic hybridization (CGH) analyses showed that the appearance of somatic variations in the genomes of the iPSCs did not vary substantially according to the original cell types (LCLs, T-cells and fibroblasts). Furthermore, LiPSCs could be differentiated into functional neurons by using the direct neurosphere conversion method (dNS method), and they showed several Parkinson's disease phenotypes that were similar to those of DF-iPSCs. These data indicate that the global LCL repositories can be used as a resource for generating iPSCs and disease models. Thus, LCLs are the powerful tools for generating iPSCs and modeling neurological diseases.

DOI： 10.1186/s13041-016-0267-6

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CELL PRESS  

Modeling of neurological diseases using induced pluripotent stem cells (iPSCs) derived from the somatic cells of patients has provided a means of elucidating pathogenic mechanisms and performing drug screening. T cells are an ideal source of patient-specific iPSCs because they can be easily obtained from samples. Recent studies indicated that iPSCs retain an epigenetic memory relating to their cell of origin that restricts their differentiation potential. The classical method of differentiation via embryoid body formation was not suitable for T cell-derived iPSCs (TiPSCs). We developed a neurosphere-based robust differentiation protocol, which enabled TiPSCs to differentiate into functional neurons, despite differences in global gene expression between TiPSCs and adult human dermal fibroblast-derived iPSCs. Furthermore, neurons derived from TiPSCs generated from a juvenile patient with Parkinson's disease exhibited several Parkinson's disease phenotypes. Therefore, we conclude that TiPSCs are a useful tool for modeling neurological diseases.

DOI： 10.1016/j.stemcr.2016.01.010

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Deprivation of one modality can lead to the improvement of other intact modalities. We have previously reported that visual deprivation drives AMPA receptors into synapses from layer4 to 2/3 in the barrel cortex and sharpens functional whisker-barrel map at layer2/3 2 days after the beginning of visual deprivation. Enhanced excitatory synaptic transmission at layer4-2/3 synapses is transient and returns to the base line level a week after the beginning of visual deprivation. Here we found that sharpened whisker-barrel function is maintained at least for a week in visually deprived animals. While increased AMPA receptor-mediated synaptic transmission at layer4-2/3 synapses dropped to the base line a week after the beginning of visual deprivation, lateral inhibitory synaptic transmission onto the neighboring barrel was kept strengthened for a week of visually deprived animals. Thus, transient strengthening of excitatory synapses at layer4-2/3 in the barrel cortex could trigger the enhancement of inhibitory inputs to neighboring barrel, and sustained lateral inhibition can maintain the sharpening of whisker-barrel map in visually deprived animals.

DOI： 10.1371/journal.pone.0149068

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Experience-dependent plasticity is limited in the adult brain, and its molecular and cellular mechanisms are poorly understood. Removal of the myelin-inhibiting signaling protein, Nogo receptor (NgR1), restores adult neural plasticity. Here we found that, in NgR1-deficient mice, whisker experience-driven synaptic α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) insertion in the barrel cortex, which is normally complete by 2 weeks after birth, lasts into adulthood. In vivo live imaging by two-photon microscopy revealed more AMPAR on the surface of spines in the adult barrel cortex of NgR1-deficient than on those of wild-type (WT) mice. Furthermore, we observed that whisker stimulation produced new spines in the adult barrel cortex of mutant but not WT mice, and that the newly synthesized spines contained surface AMPAR. These results suggest that Nogo signaling limits plasticity by restricting synaptic AMPAR delivery in coordination with anatomical plasticity.

DOI： 10.1093/cercor/bhv232

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Cognitive function can be affected by the estrous cycle. However, the effect of the estrous cycle on synaptic functions is poorly understood. Here we show that in female rats, inhibitory-avoidance (IA) task (hippocampus-dependent contextual fear-learning task) drives GluA2-lacking Ca2+-permeable AMPA receptors (CP-AMPARs) into the hippocampal CA3-CA1 synapses during all periods of the estrous cycle except the proestrous period, when estrogen levels are high. In addition, IA task failed to drive CP-AMPARs into the CA3-CA1 synapses of ovariectomized rats only when estrogen was present. Thus, changes in the stoichiometry of AMPA receptors during learning depend on estrogen levels. Furthermore, the induction of long-term potentiation (LTP) after IA task was prevented during the proestrous period, while intact LTP is still expressed after IA task during other period of the estrous cycle. Consistent with this finding, rats conditioned by IA training failed to acquire hippocampus-dependent Y-maze task during the proestrous period. On the other hand, during other estrous period, rats were able to learn Y-maze task after IA conditioning. These results suggest that high estrogen levels prevent the IA learning-induced delivery of CP-AMPARs into hippocampal CA3-CA1 synapses and limit synaptic plasticity after IA task, thus preventing the acquisition of additional learning.

DOI： 10.1371/journal.pone.0131359

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Psychophysiological markers have been focused to investigate the psychopathology of psychiatric disorders and personality subtypes. In order to understand neurobiological mechanisms underlying these conditions, fear-conditioning model has been widely used. However, simple aversive stimuli are too simplistic to understand mechanisms because most patients with psychiatric disorders are affected by social stressors. The objective of this study was to test the feasibility of a newly-designed conditioning experiment using a stimulus to cause interpersonal conflicts and examine associations between personality traits and response to that stimulus. Twenty-nine healthy individuals underwent the fear conditioning and extinction experiments in response to three types of stimuli: a simple aversive sound, disgusting pictures, and pictures of an actors' face with unpleasant verbal messages that were designed to cause interpersonal conflicts. Conditioned response was quantified by the skin conductance response (SCR). Correlations between the SCR changes, and personality traits measured by the Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD) and Revised NEO Personality Inventory were explored. The interpersonal conflict stimulus resulted in successful conditioning, which was subsequently extinguished, in a similar manner as the other two stimuli. Moreover, a greater degree of conditioned response to the interpersonal conflict stimulus correlated with a higher ZAN-BPD total score. Fear conditioning and extinction can be successfully achieved, using interpersonal conflicts as a stimulus. Given that conditioned fear caused by the interpersonal conflicts is likely associated with borderline personality traits, this paradigm could contribute to further understanding of underlying mechanisms of interpersonal fear implicated in borderline personality disorder.

DOI： 10.1371/journal.pone.0125729

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Background: General anesthesia induces long-lasting cognitive and learning deficits. However, the underlying mechanism remains unknown. The GluA1 subunit of AMPAR is a key molecule for learning and synaptic plasticity, which requires trafficking of GluA1-containing AMPARs into the synapse.
Methods: Adult male rats were exposed to 1.8% isoflurane for 2 h and subjected to an inhibitory avoidance task, which is a hippocampus-dependent contextual fear learning paradigm (n = 16 to 39). The in vitro extracellular field potential of hippocampal synapses between the Schaffer collateral and the CA1 was evaluated using a multielectrode recorder (n = 6 per group). GluA1 expression in the synaptoneurosome was assessed using Western blotting (n = 5 to 8). The ubiquitination level of GluA1 was evaluated using immunoprecipitation and Western blotting (n = 7 per group).
Results: Seven days after exposure to 1.8% isoflurane for 2 h (Iso(1.8)), the inhibitory avoidance learning (control vs. Iso(1.8); 294 +/- 34 vs. 138 +/- 28, the mean +/- SEM [%]; P = 0.002) and long-term potentiation (125.7 +/- 6.1 vs. 105.7 +/- 3.3; P < 0.001) were impaired. Iso(1.8) also temporarily increased GluA1 in the synaptoneurosomes (100 +/- 9.7 vs. 138.9 +/- 8.9; P = 0.012) and reduced the GluA1 ubiquitination, a main degradation pathway of GluA1 (100 +/- 8.7 vs. 71.1 +/- 6.1; P = 0.014).
Conclusions: Isoflurane impairs hippocampal learning and modulates synaptic plasticity in the postanesthetic period. Increased GluA1 may reduce synaptic capacity for additional GluA1-containing AMPARs trafficking.

DOI： 10.1097/ALN.0000000000000269

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Reproductive success depends on a robust and appropriately timed preovulatory luteinizing hormone (LH) surge, which is induced by the activation of gonadotropin-releasing hormone (GnRH) neurons in response to positive feedback from increasing estrogen levels. Here we document an increase in postsynaptic GluR2-lacking Ca2+-permeable AMPA-type glutamate receptors (CP-AMPARs) at synapses on GnRH neurons on the day of proestrus in rats, coincident with the increase in estrogen levels. Functional blockade of CP-AMPARs depressed the synaptic responses only on the day of proestrus and concomitantly attenuated the LH surge. Thus, the phasic synaptic incorporation of postsynaptic CP-AMPARs on GnRH neurons is involved in the generation of the LH surge. © 2013 The Authors.

DOI： 10.1016/j.neuroscience.2013.06.040

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

In neonates, the stress of social isolation can alter developing neural circuits and cause mental illness. However, the molecular and cellular bases for these effects are poorly understood. Experience-driven synaptic AMPA receptor delivery is crucial for circuit organisation during development. In the rat, whisker experience drives the delivery of glutamate receptor subunit 4 (GluA4) but not glutamate receptor subunit 1 (GluA1) to layer 42/3 pyramidal synapses in the barrel cortex during postnatal day (P)810, whereas GluA1 but not GluA4 is delivered to these synapses during P1214. We recently reported that early social isolation disrupts experience-driven GluA1 delivery to layer 42/3 pyramidal synapses during P1214. Here, we report that neonatal isolation affects even earlier stages of development by preventing experience-dependent synaptic GluA4 delivery. Thus, social isolation severely affects synaptic maturation throughout early postnatal development.

DOI： 10.1111/ejn.12188

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Nature Publishing Group  

Learning induces plastic changes in synapses. However, the regulatory molecules that orchestrate learning-induced synaptic changes are largely unknown. Although it is well established that cholinergic inputs from the medial septum modulate learning and memory, evidence for the cholinergic regulation of learning-induced synaptic plasticity is lacking. Here we find that the activation of muscarinic acetylcholine (ACh) receptors (mAChRs) mediates the contextual fear learning-driven strengthening of hippocampal excitatory pyramidal synapses through the synaptic incorporation of AMPA-type glutamate receptors (AMPARs). Contextual fear learning also enhances the strength of inhibitory synapses on hippocampal pyramidal CA1 neurons, in a manner mediated by the activation of, not mAChRs, but, nicotinic AChRs (nAChRs). We observe a significant correlation between the learning-induced increases in excitatory and inhibitory synaptic strength at individual pyramidal neurons. Understanding the mechanisms underlying cholinergic regulation of learning-induced hippocampal synaptic plasticity may help the development of new therapies for cognitive disorders. © 2013 Macmillan Publishers Limited. All rights reserved.

DOI： 10.1038/ncomms3760

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC CLINICAL INVESTIGATION INC  

Stressful events during early childhood can have a profound lifelong influence on emotional and cognitive behaviors. However, the mechanisms by which stress affects neonatal brain circuit formation are poorly understood. Here, we show that neonatal social isolation disrupts molecular, cellular, and circuit developmental processes, leading to behavioral dysfunction. Neonatal isolation prevented long-term potentiation and experience-dependent synaptic trafficking of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors normally occurring during circuit formation in the rodent barrel cortex. This inhibition of AMPA receptor trafficking was mediated by an increase of the stress glucocorticoid hormone and was associated with reduced calcium/calmodulin-dependent protein kinase type II (CaMKII) signaling, resulting in attenuated whisker sensitivity at the cortex. These effects led to defects in whisker-dependent behavior in juvenile animals. These results indicate that neonatal social isolation alters neuronal plasticity mechanisms and perturbs the initial establishment of a normal cortical circuit, which potentially explains the long-lasting behavioral effects of neonatal stress.

DOI： 10.1172/JCI63060

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

During early postnatal brain development, experience-driven delivery of AMPA receptors to synapses participates in the initial organization of conical function. By combining virus-mediated in vivo gene delivery with in vitro whole cell recordings, we identified a subunit-specific developmental program of experience-driven AMPA receptor delivery to synapses in rat barrel cortex. We expressed green fluorescent protein (GFP)-tagged AMPA receptors (GFP-GluR1, or GFP-GluR4) into layer 2/3 pyramidal neurons at two distinct developmental periods, postnatal day (P)8-P10 and P12-P14. Two days after viral infection, acute brain slices were prepared, and synaptic transmission from layer 4 to layer 2/3 was analyzed by whole cell recordings. We found that whisker experience drives GluR4 but not GluR1 into these synapses early in postnatal development (P8-1310). However, at P12-14, GluR1 but not GluR4 is delivered into synapses by whisker experience. This precise developmental plan suggests unique plasticity properties endowed in different AMPA receptor subunits which shape the initial experience-driven organization of cortical function. (C) 2011 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.brainres.2011.11.033

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DOI： 10.4161/cib.4.4.15470

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATL ACAD SCIENCES  

The hippocampus plays a central role in learning and memory. Although synaptic delivery of AMPA-type glutamate receptors (AMPARs) contributes to experience-dependent synaptic strengthening, its role in hippocampus-dependent learning remains elusive. By combining viral-mediated in vivo gene delivery with in vitro patch-clamp recordings, we found that the inhibitory avoidance task, a hippocampus-dependent contextual fear-learning paradigm, delivered GluR1-containing AMPARs into CA3-CA1 synapses of the dorsal hippocampus. To block the synaptic delivery of endogenous AMPARs, we expressed a fragment of the GluR1-cytoplasmic tail (the 14-aa GluR1 membrane-proximal region with two serines mutated to phospho-mimicking aspartates: MPR-DD). MPR-DD prevented learning-driven synaptic AMPAR delivery in CA1 neurons. Bilateral expression of MPR-DD in the CA1 region of the rat impaired inhibitory avoidance learning, indicating that synaptic GluR1 trafficking in the CA1 region of the hippocampus is required for encoding contextual fear memories. The fraction of CA1 neurons that underwent synaptic strengthening positively correlated with the performance in the inhibitory avoidance fear memory task. These data suggest that the robustness of a contextual memory depends on the number of hippocampal neurons that participate in the encoding of a memory trace.

DOI： 10.1073/pnas.1104558108

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CELL PRESS  

Loss of one type of sensory input can cause improved functionality of other sensory systems. Whereas this form of plasticity, cross-modal plasticity, is well established, the molecular and cellular mechanisms underlying it are still unclear. Here, we show that visual deprivation (VD) increases extracellular serotonin in the juvenile rat barrel cortex. This increase in serotonin levels facilitates synaptic strengthening at layer 4 to layer 2/3 synapses within the barrel cortex. Upon VD, whisker experience leads to trafficking of the AMPA-type glutamate receptors (AMPARs) into these synapses through the activation of ERK and increased phosphorylation of AMPAR subunit GluR1 at the juvenile age when natural whisker experience no longer induces synaptic GluR1 delivery. VD thereby leads to sharpening of the functional whisker-barrel map at layer 2/3. Thus, sensory deprivation of one modality leads to serotonin release in remaining modalities, facilitates GluR1-dependent synaptic strengthening, and refines cortical organization.

DOI： 10.1016/j.neuron.2011.01.016

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

Neurons communicate with each other through synapses. To establish the precise yet flexible connections that make up neural networks in the brain, continuous synaptic modulation is required. The ubiquitin-proteasome system of protein degradation is one of the critical mechanisms that underlie this process, playing crucial roles in the regulation of synaptic structure and function. We identified a novel ubiquitin ligase, Fbxo45, that functions at synapses. Fbxo45 is evolutionarily conserved and selectively expressed in the nervous system. We demonstrated that the knockdown of Fbxo45 in primary cultured hippocampal neurons resulted in a greater frequency of miniature excitatory postsynaptic currents. We also found that Fbxo45 induces the degradation of a synaptic vesicle-priming factor, Munc13-1. We propose that Fbxo45 plays an important role in the regulation of neurotransmission by modulating Munc13-1 at the synapse.

DOI： 10.1074/jbc.M109.046284

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Language：English   Publisher：ELSEVIER IRELAND LTD  

DOI： 10.1016/j.neures.2010.07.1261

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL PUBLISHING, INC  

Differences in male and female responses to pain are widely recognized in many species, including humans, but the cerebral mechanisms that generate these responses are unknown. Using the formalin test, we confirmed that proestrus female rats showed nociceptive behavior, modulated by estrogen that was distinct from male rats, particularly during the interphase period. We then explored the brain areas, which were involved in the female pattern of nociceptive behavior. We found that, after a formalin injection and at the time corresponding to the behavioral interphase, the number of phosphorylated cAMP response element-binding protein (pCREB)-immunoreactive neurons observed by immunocytochemistry increased in the dorsolateral division of the bed nucleus of the stria terminalis (BSTLD) in female but not male rats. There were no significant sex differences in pCREB expression following formalin in any region other than the BSTLD. The increased pCREB in female rats was eliminated after an ovariectomy and restored with 17 beta-estradiol treatment. Neither an orchidectomy nor 17 beta-estradiol treatment affected the pCREB response in male rats. The increase in pCREB expression in the BSTLD in female rats after formalin injection was confirmed with immunoblotting. To determine the role of CREB in the BSTLD, adenovirus-mediated expression of a dominant-negative form of CREB (mCREB) was carried out. The nociceptive behavior during interphase was significantly attenuated by injection of virus carrying mCREB into the BSTLD in female rats but not in male rats. These results suggest a novel role for CREB in the BSTLD as a modulator of the pain response in a female-specific, estrogen-dependent manner.

DOI： 10.1111/j.1460-9568.2009.07002.x

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Language：English   Publisher：WILEY-BLACKWELL PUBLISHING, INC  

Acetylcholine (ACh) release in the dorsal hippocampus increases during stress, exploration or learning, exhibiting sex-specific 24-h release profile. We review the role of gonadal steroids on the ACh release in the dorsal hippocampus. In our studies, we found that male rats showed higher extracellular ACh levels than females, but gonadectomy decreased ACh levels in both sexes of rats and subsequently eliminated the sex difference. To examine the sex difference under comparable gonadal steroid levels, we implanted steroid capsules after gonadectomy. Oestradiol supplementation maintained circulating oestradiol to the levels in proestrous female rats, whereas testosterone capsules maintained circulating testosterone to the levels similar to intact male rats. Under comparable gonadal steroids levels, ACh levels were sex-specific. Testosterone replacement in orchidectomised rats clearly restored ACh levels, which were greater than ovariectomised testosterone-primed rats. Similarly, oestradiol replacement in ovariectomised rats successfully restored ACh levels, which were higher than orchidectomised oestradiol-primed rats. These results suggest sex-specific activational effects of gonadal steroids on ACh release. To further examine the organisational effect, female pups were neonatally treated with oil, testosterone, oestradiol, or dihydrotestosterone. These rats were bilaterally ovariectomised and a testosterone capsule was implanted at postnatal week 8. Neonatal treatment of either testosterone or oestradiol clearly increased ACh levels, whereas neonatal dihydrotestosterone treatment failed to change levels. These results suggest that: (i) gonadal steroids maintain the sex-specific ACh release in the dorsal hippocampus and (ii) neonatal activation of oestrogen receptors is sufficient to mediate masculinisation of the septo-hippocampal cholinergic system.

DOI： 10.1111/j.1365-2826.2009.01848.x

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Acetylcholine (ACh) release in the dorsal hippocampus increases during stress, exploration or learning, exhibiting sex-specific 24-h release profile. We review the role of gonadal steroids on the ACh release in the dorsal hippocampus. In our studies, we found that male rats showed higher extracellular ACh levels than females, but gonadectomy decreased ACh levels in both sexes of rats and subsequently eliminated the sex difference. To examine the sex difference under comparable gonadal steroid levels, we implanted steroid capsules after gonadectomy. Oestradiol supplementation maintained circulating oestradiol to the levels in proestrous female rats, whereas testosterone capsules maintained circulating testosterone to the levels similar to intact male rats. Under comparable gonadal steroids levels, ACh levels were sex-specific. Testosterone replacement in orchidectomised rats clearly restored ACh levels, which were greater than ovariectomised testosterone-primed rats. Similarly, oestradiol replacement in ovariectomised rats successfully restored ACh levels, which were higher than orchidectomised oestradiol-primed rats. These results suggest sex-specific activational effects of gonadal steroids on ACh release. To further examine the organisational effect, female pups were neonatally treated with oil, testosterone, oestradiol, or dihydrotestosterone. These rats were bilaterally ovariectomised and a testosterone capsule was implanted at postnatal week 8. Neonatal treatment of either testosterone or oestradiol clearly increased ACh levels, whereas neonatal dihydrotestosterone treatment failed to change levels. These results suggest that: (i) gonadal steroids maintain the sex-specific ACh release in the dorsal hippocampus and (ii) neonatal activation of oestrogen receptors is sufficient to mediate masculinisation of the septo-hippocampal cholinergic system.

DOI： 10.1111/j.1365-2826.2009.01848.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

The medial prefrontal cortex (mPFC) controls emotional responses in many species, receiving serotonergic innervation from the dorsal and median raphe nucleus (DRN and MRN). To examine the sex difference in 24-h profiles of extracellular serotonin (5HT) levels in the mPFC, an in vivo microdialysis study was performed using intact male, diestrous female, and proestrous female rats. Dialysates were automatically collected by a microdialysis probe from the mPFC every 30 min for more than 24 h under freely moving conditions. The levels of 5HT in dialysates were quantified by high performance liquid chromatography. Extracellular 5HT levels exhibited episodic changes in the mPFC of both sexes of rats, with both diestrous and proestrous females exhibiting a clear diurnal change; the 5HT levels were high during the dark phase, but low during the light phase. In contrast, male rats exhibited relatively high 5HT levels throughout the day without significant diurnal changes. At mathematically analyzed trough, males showed higher 5HT levels than diestrous or proestrous females. The overall 24-h 5HT levels in males were significantly greater than proestrous females, but were not different from diestrous females. Further, stereological methods were used to examine the number of tryptophan hydroxylase (TrpH), but no sex differences in the number of TrpH immunoreactive cells in the DRN and MRN were observed. These results suggest that sex and/or the gonadal steroid environment may affect the 24-h profile of extracellular 5HT in the mPFC of rats without changes in the number of 5HT neurons in the DRN and MRN. (C) 2009 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.brainres.2008.12.084

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

Nicotinic cholinergic receptors play a role in cardiovascular regulation in the lower brain stem. Herein, we present evidence that L-3,4-dihydroxyphenylatanine (DOPA), a putative neurotransmitter in the central nervous system, is involved in the depressor response to microinjection of nicotine into the nucleus tractus solitarii (NTS). Microinjection of nicotine into the medial area of the NTS led to decreases in arterial blood pressure and heart rate in anesthetized rats. Mecamylamine, a nicotinic receptor antagonist, microinjected into NTS, blocked the depressor and bradycardic responses to nicotine. Nicotine-induced depressor and bradycardic responses were blocked by DOPA cyclohexyl ester (DOPA CHE), an antagonist for DOPA. DOPA CHE did not modify the action of carbachol on excitatory postsynaptic potential in rat cortical slices. These results suggest that endogenous DOPA is involved in nicotine-induced depressor responses in the NTS of anesthetized rats. (c) 2008 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.neulet.2008.06.077

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SOC NEUROSCIENCE  

Collapsin response mediator protein 1(CRMP1) is one of the CRMP family members that mediates signal transduction of axonal guidance and neuronal migration. We show here evidence that CRMP1 is involved in semaphorin3A (Sema3A)-induced spine development in the cerebral cortex. In the cultured cortical neurons from crmp1(+/-) mice, Sema3A increased the density of clusters of synapsin I and postsynaptic density-95, but this increase was markedly attenuated in crmp1(-/-) mice. This attenuation was also seen in cyclin-dependent kinase 5 (cdk5)(-/-) neurons. Furthermore, the introduction of wild-type CRMP1 but not CRMP1-T509A/S522A, (Thr 509 and Ser 522 were replaced by Ala), a mutant that cannot be phosphorylated by Cdk5, into crmp1(-/-) neurons rescued the defect in Sema3A responsiveness. The Golgi-impregnation method showed that the crmp1(-/-) layer V cortical neurons showed a lower density of synaptic bouton-like structures and that this phenotype had genetic interaction with sema3A. These findings suggest that Sema3A-induced spine development is regulated by phosphorylation of CRMP1 by Cdk5.

DOI： 10.1523/JNEUROSCI.3463-07.2007

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Collapsin response mediator protein 1 ( CRMP1) is one of the CRMP family members that mediates signal transduction of axon guidance molecules. Here, we show evidence that CRMP1 is involved in Reelin ( Reln) signaling to regulate neuronal migration in the cerebral cortex. In crmp1(-/-) mice, radial migration of cortical neurons was retarded. This phenotype was not observed in the sema3A(-/-) and crmp1(+/+); sema3A(+/+) cortices. However, CRMP1 was colocalized with disabled- 1 ( Dab1), an adaptor protein in Reln signaling. In the Reln(rl/rl) cortex, CRMP1 and Dab1 were expressed at a higher level, yet tyrosine phosphorylated at a lower level. Loss of crmp1 in a dab1 heterozygous background led to the disruption of hippocampal lamination, a Reeler- like phenotype. In addition to axon guidance, CRMP1 regulates neuronal migration by mediating Reln signaling.

DOI： 10.1523/JNEUROSCI.4276-06.2006

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC ADVANCEMENT SCIENCE  

The mechanisms underlying experience-dependent plasticity in the brain may depend on the AMPA subclass of glutamate receptors (AMPA-Rs). We examined the trafficking of AMPA-Rs into synapses in the developing rat barrel cortex. In vivo gene delivery was combined with in vitro recordings to show that experience drives recombinant GluR1, an AMPA-R subunit, into synapses formed between layer 4 and layer 2/3 neurons. Moreover, expression of the GluR1 cytoplasmic tail, a construct that inhibits synaptic delivery of endogenous AMPA-Rs during long-term potentiation, blocked experience-driven synaptic potentiation. In general, synaptic incorporation of AMPA-Rs in vivo conforms to rules identified in vitro and contributes to plasticity driven by natural stimuli in the mammalian brain.

DOI： 10.1126/science.1079886

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CELL PRESS  

Semaphorin 3A (Sema3A) binds to neuropilin-1 (NP1) and activates the transmembrane Plexin to transduce a repulsive axon guidance signal. Here, we show that Sema3 signals are transduced equally effectively by PlexinA1 or PlexinA2, but not by PlexinA3. Deletion analysis of the PlexinA1 ectodomain demonstrates that the sema domain prevents PlexinA1 activation in the basal state. Sema-deleted PlexinA1 is constitutively active, producing cell contraction, growth cone collapse, and inhibition of neurite outgrowth. The sema domain of PlexinA1 physically associates with the remainder of the PlexinA1 ectodomain and can reverse constitutive activation. Both the sema portion and the remainder of the ectodomain of PlexinA1 associate with NP1 in a Sema3A-independent fashion. Plexin Al is autoinhibited by its sema domain, and Sema3A/NP1 releases this inhibition.

DOI： 10.1016/S0896-6273(01)00216-1

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Class 1 and 3 semaphorins repulse axons but bind to different cell surface proteins. We find that the two known semaphorin-binding proteins, plexin 1 (Plex 1) and neuropilin-1 (NP-1), form a stable complex. Plex 1 alone does not bind semaphorin-3A (Sema3A), but the NP-1/Plex 1 complex has a higher affinity for Sema3A than does NP-1 alone. While Sema3A binding to NP-1 does not alter nonneuronal cell morphology, Sema3A interaction with NP-1/Plex 1 complexes induces adherent cells to round up. Expression of a dominant-negative Plex 1 in sensory neurons blocks Sema3A-induced growth cone collapse. Sema3A treatment leads to the redistribution of growth cone NP-1 and plexin into clusters. Thus, physiologic Sema3A receptors consist of NP-1/plexin complexes.

DOI： 10.1016/S0092-8674(00)80062-8

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JOHN WILEY & SONS INC  

Collapsin-1/Sema III, a member of the semaphorin family, has been implicated in axonal path-finding as a repulsive guidance cue. Cellular and molecular mechanisms by which collapsin-1 exerts its action are not fully understood. Collapsin-1 induces growth cone collapse via a pathway which may include neuropilin-1, a cell-surface collapsin-1 binding protein, as well as intracellular CRMP-62 and heterotrimeric G proteins. We previously identified a second action of collapsin-1, the facilitation of antero- and retrograde axoplasmic transport. This response occurs via a mechanism distinct from that causing growth cone collapse. To investigate the possible involvement of neuropilin-1 in the action of collapsin-1 on axoplasmic transport, we produced a soluble neuropilin-1 (sNP-1) lacking the transmembrane and intracellular region. sNP-1 progressively displaced the dose-response curve for collapsin-1 eo induce growth cone collapse to higher concentrations, sNP-1 also inhibited collapsin-1-induced augmentation of both antero- and retrograde axoplasmic transport. Furthermore, an anti-neuropilin-1 antibody blocked the collapsin-induced axoplasmic transport. These results together indicate that neuropilin-1 mediates collapsin-1 action on axoplasmic transport. To visualize collapsin-1 binding to endogenous neuropilin-1, we used a truncated collapsin-1-alkaline phosphatase fusion protein (CAP-4). CAP-4 stains the growth cone, neurite, and cell body. However, local application of collapsin-1 to growth cone but to neither neurite nor cell body promotes axoplasmic transport. Thus, growth cone NP-1 mediates the facilitatory action of collapsin-1 on antero- and retrograde axoplasmic transport, (C) 1999 John Wiley & Sons. Inc.

DOI： 10.1002/(SICI)1097-4695(19990615)39:4<579::AID-NEU11>3.0.CO;2-9

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Somatosensory axon outgrowth is repulsed when soluble semaphorin D (semD) binds to growth cone neuropilin-1 (Npn-1). Here, semD ligand binding studies of Npn-1 mutants demonstrate that the sema domain binds to the amino-terminal quarter, or complement-binding (CUB) domain, of Npn-1. By herpes simplex virus- (HSV-) mediated expression of Npn-1 mutants in chick retinal ganglion cells, we show that semD-induced growth cone collapse requires two segments of the ectodomain of Npn-1, the CUB domain and the juxtamembrane portion, or MAM (meprin, A5, mu) domain. In contrast, the transmembrane segment and cytoplasmic tail of Npn-1 are not required for biologic activity. These data imply that the CUB and MAM ectodomains of Npn-1 interact with another transmembrane growth cone protein that in turn transduces a semD signal into axon repulsion.

DOI： 10.1016/S0896-6273(00)80626-1

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE AMERICA INC  

Neuropilin-1 (NP-1) has been identified as a necessary component of a semaphorin D (SemD) receptor; that repulses dorsal root ganglion (DRG) axons during development. SemA and SemE are related to SemD and bind to NP-1, but do not repulse DRG axons. By expressing NP-1 in retinal neurons and NP-2 in DRG neurons, we demonstrate that neuropilins are sufficient to determine the functional specificity of semaphorin responsiveness. SemA and SemE block SemD binding to NP-1 and abolish SemD repulsion in axons expressing NP-1. SemA and SemE seem to have a newly discovered protein antagonist capacity at NP-1 receptors, whereas they act as agonists at receptors containing NP-2.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SOC NEUROSCIENCE  

The collapsin and semaphorin family of extracellular proteins contributes to axonal path finding by repulsing axons and collapsing growth cones. To explore the mechanism of collapsin-1 action, we expressed and purified a truncated collapsin-1-alkaline phosphatase fusion protein (CAP-4). This protein retains biological activity as a DRG growth cone collapsing agent and saturably binds to DRG neurons with low nanomolar affinity. Specific CAP-4 binding sites are present on DRG neurons, sympathetic neurons, and motoneurons, but not on retinal, cortical, or brainstem neurons. Outside the nervous system, high levels of CAP-4 binding sites are present in the mesenchyme surrounding major blood vessels and developing bone and in lung. These sites provide a substrate for the collapsin-1-dependent patterning of non-neuronal tissues perturbed in sema III (-/-) mice. The staining patterns for mouse semaphorin D/III and chick collapsin-1 fusion proteins are indistinguishable from one another but quite separate from that for semaphorin B and M-semaphorin F fusion proteins. These data imply that a family of high-affinity semaphorin binding sites similar in complexity to the semaphorin ligand family exists.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

The Drosophila melanogaster (Dot) decapentaplegic (dpp) gene product plays an essential role during several stages of Dm development. The DPP protein is a member of the transforming growth factor-beta (TGF-beta) superfamily and an orthologue of mammalian bone morphogenetic proteins (BMP-2 and -4). Recently, a cDNA clone encoding the mouse Ser/Thr kinase receptor specific for BMP-2/-4 (mTFR11) was isolated. Here, we describe the deduced primary structure, the cytogenetic position and expression pattern of the Dm homologue of mTFR11 (DTFR), a putative DPP receptor. The cytogenetic position of the Dm dtfr gene was mapped to 25D. DTFR has striking homology to mTFR11, especially in the cytoplasmic domain (approx. 63%), including a Ser + Gly-rich box that is characteristic of type-I receptors for the TGF-P superfamily. Although the amino acid (aa) sequence of the extracellular domain is less conserved than that of the cytoplasmic domain, the extracellular domains of these two molecules were more homologous (approx. 27%) to each other than any other receptors for the TGF-beta superfamily. The spacing of Cys residues in the extracellular domain, which is considered crucial to ligand specificity, is highly conserved in these two receptors. During Dm embryonic development, its expression pattern changes in a dynamic fashion with high levels of expression in mesoderm and midgut, with some relation to dpp mutant phenotypes.

DOI： 10.1016/0378-1119(94)90690-4

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PLENUM PUBL CORP  

In housekeeping and many tissue-specific genes, the promoter is embedded in a so-called CpG island. We have compared the available human and mouse DNA sequences with respect to their CpG island properties. While mouse sequences showed a simple gradient distribution of G + C content and CpG densities, man had a distinct peak of sequences with typical CpG island characteristics. Pairwise comparison of 23 orthologous genes revealed that mouse almost always had a less pronounced CpG island than man, or none at all. In both species the requirements for a functional CpG island may be similar in that most DNA regions with a density of six or more CpG per 100 bp remain unmethylated. However, the mouse has apparently experienced more accidental CpG island methylation, suggested by local TpG and CpA excess. We propose that: (1) in mouse the CpG islands do not represent the ancestral state but have been eroded during evolution, and (2) this erosion may be related to the mouse's small body mass and short life-span, allowing for a more relaxed control of gene activity.

DOI： 10.1007/BF01233381

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Language：Japanese  

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J-GLOBAL

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Language：Japanese   Publisher：(株)アドスリー  

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Language：Japanese   Publisher：(株)ニュー・サイエンス社  

精神神経疾患には難治性にものも多く、創薬を含めたその診断・治療法開発のためには強固な科学的根拠が必要である。グルタミン酸シナプスは脳内の興奮性シナプスの大半を占めると言われている。グルタミン酸に結合し、情報伝達を担うグルタミン酸受容体は何種類か存在する。その中でもAMPA受容体(α-Amino-3-hydroxy-5-Methyl-4-isoxazolepropionic Acid Receptor)はグルタミン酸シナプス伝達において特に重要な役割を担っている。AMPA受容体は脳内情報伝達の最重要分子であり、その機能の破綻は多くの精神神経疾患に関わっているということが実験動物を用いた基礎研究において示唆されているが、臨床応用に結びついている例は稀有である。その大きな要因は、ヒト生体脳でAMPA受容体を可視化・定量化する技術が存在していないため、ヒト疾患におけるAMPA受容体の役割が不明であったからである。筆者らは最近、ヒト生体でAMPA受容体を可視化・定量化する世界初の技術となるポジトロン断層撮影(PET)用プローブ、[11C]K-2の開発に成功した。(著者抄録)

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Language：Japanese   Publisher：(株)ニュー・サイエンス社  

脳卒中は運動麻痺や高次脳機能障害などを特徴とする脳血管障害である。脳卒中により生じた運転麻痺は元の水準までの運動機能回復は困難である。運動機能回復を促進する治療戦略が考案されているが、臨床現場への還元は未だ障壁が高い現状にある。より効果的な治療法の発展には、脳損傷後のリハビリテーションによる運動機能回復が促進されるメカニズムの理解に基づいた治療薬の開発が必須と考える。筆者らは、マウス一次運動野損傷モデル及び霊長類内包出血モデルを用いて、AMPA(α-3-hydroxy-5-methyl-4-isoxazole propionic acid)受容体のシナプス移行を促進することで運動機能回復を促進する新規化合物Edonerpic maleate(T-817MA; 1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}azetidin-3-ol maleate)の開発に成功した。(著者抄録)

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Language：Japanese   Publisher：(一社)日本頭痛学会  

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Language：Japanese   Publisher：(公社)日本精神神経学会  

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Language：Japanese   Publisher：日本うつ病学会・日本認知療法・認知行動療法学会  

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Language：Japanese   Publisher：(株)中外医学社  

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Language：Japanese   Publisher：医歯薬出版(株)  

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Language：Japanese   Publisher：日本臨床外科学会  

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Language：Japanese   Publisher：Japanese Association of Physical Therapy Fundamentals  

The central nervous system injury such as stroke can severely cause the motor paralysis. Although the approach of the rehabilitative training is developed, many patients still face the restrictions in their daily living after rehabilitation. Thereby, a new compound with strong potential to enhance motor function recovery with rehabilitation is an unmet medical needs. We focus on the one of glutamate receptors, AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor, which plays an important role in learning and memory. Here, we found a novel small low molecular compound, edonerpic-maleic acid edonerpic MA), facilitated experience-dependent synaptic AMPA receptor delivery in barrel cortex and dramatically accelerated motor function recovery after brain damage in rodent model. Furthermore, edonerpic MA enhanced the upper limb function recovery of macaque monkeys with the internal capsule hemorrhage. Currently, a phase 2 clinical trial is being conducted to verify the efficacy of edonerpic MA in stroke patients and has attracted global attention.

DOI： 10.24780/jptf.23.1_37

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J05805&link_issn=&doc_id=20210319280006&doc_link_id=%2Fch1thrpy%2F2020%2F002301%2F006%2F0037-0045%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fch1thrpy%2F2020%2F002301%2F006%2F0037-0045%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(一社)日本認知症学会  

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Language：Japanese   Publisher：(株)中外医学社  

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Language：Japanese   Publisher：(株)ニュー・サイエンス社  

根本的治療法が存在しない神経疾患では機能障害の後遺は避け難い。機能障害を改善・代償するには疾患の進行や再発を抑制する治療に加えて、リハビリテーションが重要である。近年、脳卒中に限らず、脊髄小脳変性症、パーキンソン病、多発性硬化症といった慢性進行性疾患でもリハビリテーション法の改良が試みられている。脳神経科学ではリハビリテーションによる機能回復は非障害脳領域における機能的再構築に依拠するとされてきたが、ヒト生体脳において疾患毎の機能回復能の神経生理学的理解は不十分である。我々は、急性脳損傷モデルにおいて、グルタミン酸AMPA受容体のシナプス後膜への移行促進がリハビリテーションによる運動機能回復を促進することを薬理学的に示した。現在はこの研究に動機づけられ、PET画像で得られるAMPA受容体発現密度分布を手掛かりとして、リハビリテーションを可能とする「機能回復ネットワーク」の疾患横断的解明に取り組んでいる。(著者抄録)

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Language：Japanese   Publisher：(一社)日本小児神経学会  

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Language：Japanese   Publisher：エーザイ(株)  

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Language：Japanese   Publisher：(株)ニュー・サイエンス社  

シナプスは神経細胞同士をつないでいる構造体である。シナプス前神経に興奮が伝わると、神経伝達物質がシナプス終末から放出され、受け手の神経のシナプス後膜にある受容体に結合する。そしてイオンチャネルを形成している受容体が開き、イオンが細胞内に流入してくる。興奮性グルタミン酸シナプスは脳内シナプスの大半を占めると言われており、グルタミン酸受容体の一つがAMPA受容体(α-Amino-3-hydroxy-5-Methyl-4-isoxazolepropionic Acid Receptor)である。本稿ではAMPA受容体を切り口としたシナプス研究の概念をヒト疾患の病態解明・革新的診断・治療法開発へと繋げていく挑戦について概説する。(著者抄録)

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Language：Japanese   Publisher：エーザイ(株)  

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Language：Japanese   Publisher：(株)メディカルレビュー社  

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J05023&link_issn=&doc_id=20191113270003&doc_link_id=%2Fai1epild%2F2019%2F001302%2F004%2F0081-0086%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fai1epild%2F2019%2F001302%2F004%2F0081-0086%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：メディカルレビュー社  

CiNii Books

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Language：Japanese   Publisher：(一社)日本核医学会  

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Language：Japanese   Publisher：日本臨床精神神経薬理学会・日本神経精神薬理学会  

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Language：Japanese   Publisher：(公社)日本リハビリテーション医学会  

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Language：Japanese   Publisher：(公社)日本リハビリテーション医学会  

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Language：Japanese   Publisher：日本臨床分子医学会  

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Language：Japanese   Publisher：医歯薬出版(株)  

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J00060&link_issn=&doc_id=20190218030009&doc_link_id=issn%3D0039-2359%26volume%3D268%26issue%3D7%26spage%3D585&url=http%3A%2F%2Fwww.pieronline.jp%2Fopenurl%3Fissn%3D0039-2359%26volume%3D268%26issue%3D7%26spage%3D585&type=PierOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00005_2.gif

Language：Japanese   Publisher：日本臨床精神神経薬理学会・日本神経精神薬理学会  

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Language：Japanese   Publisher：(一社)日本核医学会  

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Language：Japanese   Publisher：(株)先端医学社  

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Language：Japanese   Publisher：(公社)日本リハビリテーション医学会  

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Language：Japanese   Publisher：生命科学系学会合同年次大会運営事務局  

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Language：English   Publisher：(一社)日本てんかん学会  

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Language：Japanese   Publisher：(一社)日本理学療法学会連合  

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Language：Japanese  

CiNii Books

CiNii Research

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Language：Japanese  

J-GLOBAL

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Language：Japanese   Publisher：(株)羊土社  

グルタミン酸作動性シナプスは脳内興奮性シナプスの約9割を占める。AMPA型グルタミン酸受容体(AMPA受容体)はグルタミン酸受容体の1つであり、神経活動の「実行部隊」ともいえる中心的な仲介役である。脳が外界からの刺激を受けて変化する「可塑性」の分子細胞基盤として「AMPA受容体のシナプスへの移行」があるが、本総説ではこの「AMPA受容体のシナプス移行」とさまざまな行動、環境との関係について概説する。(著者抄録)

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：OXFORD UNIV PRESS  

Web of Science

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Language：Japanese   Publisher：Japanese Society of Neurological Therapeutics  

DOI： 10.15082/jsnt.33.3_394

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2016&ichushi_jid=J02615&link_issn=&doc_id=20170202470030&doc_link_id=10.15082%2Fjsnt.33.3_394&url=https%3A%2F%2Fdoi.org%2F10.15082%2Fjsnt.33.3_394&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Language：Japanese   Publisher：金原一郎記念医学医療振興財団 ; 1949-  

DOI： 10.11477/mf.2425200397

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Language：Japanese  

J-GLOBAL

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Language：Japanese   Publisher：日本神経治療学会  

J-GLOBAL

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Language：Japanese   Publisher：日本神経治療学会  

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Language：Japanese   Publisher：(一社)日本小児神経学会  

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Language：Japanese   Publisher：(株)中外医学社  

J-GLOBAL

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Language：English   Publisher：AMER SOC CLINICAL INVESTIGATION INC  

DOI： 10.1172/JCI76901

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Language：Japanese   Publisher：(一社)日本生理学会  

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Language：Japanese   Publisher：(一社)日本生理学会  

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Language：Japanese   Publisher：(一社)日本生理学会  

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Language：Japanese   Publisher：京都大学霊長類研究所  

CiNii Books

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Language：Japanese   Publisher：(公社)日本理学療法士協会  

DOI： 10.14900/cjpt.2012.0.48100735.0

J-GLOBAL

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：SPRINGER JAPAN KK  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：SPRINGER JAPAN KK  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：SPRINGER JAPAN KK  

Web of Science

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Language：Japanese   Publisher：(公社)日本薬理学会  

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CiNii Books

J-GLOBAL

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Publisher：6  

PubMed

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CiNii Books

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Publisher：4  

DOI： 10.4161/cib.4.4.15470

PubMed

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Language：Japanese  

J-GLOBAL

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Language：Japanese   Publisher：(株)先端医学社  

CiNii Books

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Language：English   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

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Language：Japanese   Publisher：第一三共生命科学研究振興財団  

CiNii Books

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER IRELAND LTD  

DOI： 10.1016/j.neures.2011.07.1651

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER IRELAND LTD  

DOI： 10.1016/j.neures.2011.07.1416

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER IRELAND LTD  

DOI： 10.1016/j.neures.2011.07.270

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：JAPANESE PHARMACOLOGICAL SOC  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER IRELAND LTD  

DOI： 10.1016/j.neures.2011.07.897

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER IRELAND LTD  

DOI： 10.1016/j.neures.2011.07.242

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER IRELAND LTD  

DOI： 10.1016/j.neures.2011.07.1413

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Language：English   Publisher：(公社)日本生化学会  

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Language：English   Publisher：(一社)日本神経化学会  

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Language：English   Publisher：(一社)日本神経化学会  

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Language：English   Publisher：日本神経化学会  

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Language：English   Publisher：(一社)日本神経化学会  

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Language：English   Publisher：(一社)日本神経化学会  

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Language：English   Publisher：(一社)日本神経化学会  

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Language：Japanese  

DOI： 10.11477/mf.2425100958

J-GLOBAL

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Language：Japanese   Publisher：金原一郎記念医学医療振興財団  

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Language：Japanese   Publisher：横浜市立大学医学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER IRELAND LTD  

DOI： 10.1016/j.neures.2010.07.1522

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER IRELAND LTD  

DOI： 10.1016/j.neures.2010.07.2537

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：SPRINGER TOKYO  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER IRELAND LTD  

DOI： 10.1016/j.neures.2010.07.155

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER IRELAND LTD  

DOI： 10.1016/j.neures.2010.07.1230

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER IRELAND LTD  

DOI： 10.1016/j.neures.2010.07.1776

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Language：English   Publisher：(一社)日本神経化学会  

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J-GLOBAL

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Language：Japanese   Publisher：(公財)ライフサイエンス振興財団  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：SPRINGER TOKYO  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：SPRINGER TOKYO  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER IRELAND LTD  

DOI： 10.1016/j.neures.2009.09.156

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：SPRINGER TOKYO  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：SPRINGER TOKYO  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER IRELAND LTD  

DOI： 10.1016/j.neures.2009.09.216

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：SPRINGER TOKYO  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER IRELAND LTD  

DOI： 10.1016/j.neures.2009.09.219

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：SPRINGER TOKYO  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER IRELAND LTD  

DOI： 10.1016/j.neures.2009.09.051

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER IRELAND LTD  

DOI： 10.1016/j.neures.2009.09.1235

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：SPRINGER TOKYO  

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Language：Japanese   Publisher：(公財)上原記念生命科学財団  

過食の機序を、空腹感を形成する視床下部外側野のシナプスにα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid(AMPA)受容体(GluR1-4)が移行することにより引き起こされるという仮説をたて、それを証明した。FUGWレンチウイルスを用いて、成熟したラットの中枢神経系の特定の部位に遺伝子を発現させる方法を確立した。4時間絶食後の一過性の過食に対する効果を検討した。雌性ラットの場合、雄性ラットと比較して、24時間絶食後、一過性に有意な摂食量の増加を認め、過食のモデルとして適当であることが示唆された。対照期間3日間の摂食量を100%として表記すると、GIuR1-et群の24時間絶食後の再摂食量は、GFP対照群と比較して、有意な差を認めなかった。側坐核、視床下部弓状核、および腹側被蓋野においても同様の結果であった。

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Language：Japanese   Publisher：(株)羊土社  

われわれが新しいことを学んだり、経験するときに一体どのようなことが脳内に起こっているのであろうか?興奮性シナプスにおいて中心的役割を果たしているグルタミン酸作動性シナプスにおける可塑的変化は記録、学習をはじめとした経験依存的神経可塑性の基盤であると考えられている。グルタミン酸受容体の1つであるAMPA受容体の挙動はとりわけ注目を集めている。本稿では、記憶学習などの経験に伴って起こるAMPA受容体のシナプスへの移行について概説する。(著者抄録)

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER IRELAND LTD  

We identified a novel ubiquitin ligase (E3), Kspot as a target molecule of a high titer autoantibody produced in the serum of a patient with stomach can cer, associated with psychiatric symptoms.Kspot is highly conserved througho ut species and expressed in the mammalian nervous system. In this study we d emonstrated that Kspot formed an SCF complex and mediated ubiquitination of cellular proteins. Furthermore, overexpression of Kspot in primary cultured rat hippocampal neurons resulted in a decrease in the miniature excitatory p ostsynaptic current frequency. We propose that Kspot plays an important role in the regulation of the neurotransmitter release at the presynaptic site. &lt;b&gt;[J Physiol Sci. 2008;58 Suppl:S123]&lt;/b&gt;

Web of Science

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Publisher：PHYSIOLOGICAL SOCIETY OF JAPAN  

The brain initiates activation of the gonadotropin-releasing hormone (GnRH) system at puberty onset. Since GnRH neurons are suggested to show a plasticity during postnatal development, remodeling of GnRH neurons may be involved in the onset of puberty. The present study was done by attempting to block plasticity in the GnRH neuronal network, by interfering with the synaptic delivery of GluR1 whose trafficking is critical in synaptic plasticity and thus necessary for memory. To this end, GluR1-C-tail, a dominant negative mutant of GluR1, was expressed in the POA of female rats at day 21 using lentivirus. GluR1-C-tail has been shown to act by competing with GluR1 for synaptic delivery during synaptic plasticity. As the result, the onset of puberty, by checking viginal opening, was significantly delayed. After that, the estrous cyclicity was checked by viginal smear and found that the rat injected with GluR1-C-tail exhibited a regular estrous cycle. However, the surge of luteinizing hormone (LH) secretion in the rat injected with GluR1-C-tail was significantly attenuated, compared to the control rat. Injection with GluR1-C-tail in mature rats had no effect on the surge of LH secretion. The present study suggests that GluR1-mediated plasticity occurs at the time of puberty and is important to maintain surge of LH secretion in adults. &lt;b&gt;[J Physiol Sci. 2008;58 Suppl:S140]&lt;/b&gt;

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER IRELAND LTD  

Web of Science

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER IRELAND LTD  

Web of Science

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER IRELAND LTD  

Web of Science

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Publisher：PHYSIOLOGICAL SOCIETY OF JAPAN  

Sex differences in the response to nociceptive stimuli have long been recognized in many species. For example, in rats, females are more sensitive to formalin-induced nociceptive stimuli than males, as revealed by behavioral test. However, the neural mechanism for sex differences in the response to nociceptive stimuli was still unclear. In the previous study, we showed that females were more sensitive to formalin-induced nociceptive stimuli than males, as revealed by behavioral test. We looked for a possible sex difference in the response of the brain to formalin-induced nociceptive stimuli by checking the expression of phosphorylated cAMP response element-binding protein (pCREB) as a marker of neural activity. We found that, in the bed nucleus of the stria terminalis lateral subdivision (BSTL), the number of cells expressing pCREB was increased 5-10 min after formalin injection in female rats but not in male rats. In the present study, we examined the function of CREB in the BSTL. We found that the expression of a dominant negative form of CREB (mCREB) using adenovirus vector, significantly attenuated the response to formalin only in females but not in males, suggesting that CREB in the BSTL play a role for controlling pain-related behavior only in females. &lt;b&gt;[J Physiol Sci. 2008;58 Suppl:S165]&lt;/b&gt;

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER IRELAND LTD  

Web of Science

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Language：Japanese   Publisher：(一社)日本肥満学会  

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Language：Japanese   Publisher：東京生化学研究会  

CiNii Books

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：JAPANESE PHARMACOLOGICAL SOC  

Web of Science

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Language：Japanese   Publisher：(株)学研メディカル秀潤社  

LTPはシナプスに一定期間テタヌス刺激を加えることによりシナプス応答が長期間増強するようになるという現象で,この分子メカニズムは明らかになりつつある.in vitroで培養した海馬スライスを用いた実験により,AMPAタイプグルタミン酸受容体のGluR1がLTP誘導刺激によりシナプスに移行することが明らかになった.最近,著者等はこのGluR1のシナプス移行がin vivoにおいても経験依存的に起こっているということを見つけた.そこで,LTPと記憶の関係について最新の知見を交えて概説した

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Language：Japanese   Publisher：秀潤社  

CiNii Books

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CiNii Books

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Other Link： http://search.jamas.or.jp/link/ui/2000267642

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Language：Japanese   Publisher：(株)学研メディカル秀潤社  

CiNii Books

CiNii Research

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Language：Japanese   Publisher：(株)学研メディカル秀潤社  

CiNii Books

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Language：Japanese   Publisher：(株)学研メディカル秀潤社  

CiNii Books

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Language：Japanese   Publisher：(株)羊土社  

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Language：Japanese   Publisher：(株)メディカルレビュー社  

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