TOP ＞ Symposia

Symposia The next generation, and beyond: JSN-JPS young investigator joint symposium／次世代・その次の世代へ: 日本神経化学会ー日本薬理学会若手研究者合同シンポジウム 1S8-1 Myelination for information processing Hiroaki Wake Division of System Neuroscience Kobe University of Graduate School of Medicine Myelin sheathing is essential for our brain functions. Myelin dysregulation is frequently associated with learning deficits and cognitive dysfunctions. However, what neural activity bridges myelin dysregulation and learning deficits is unknown. Here, we used transgenic mice with subtle myelin dysregulation to measure the neural activity in the motor cortex during motor learning. Throughout training, the transgenic mice showed higher frequency of spontaneous activity and lower amplitude of movement-related activity than wild-type mice. Optogenetic activation of the thalamus, but not thalamocortical axons, dispersed the cortical activity. Repetitive photo-activation of thalamocortical axons throughout training partially restored learning. Thus, in myelin dysregulation, long-range axons with increased variability of conduction velocity raise the noise in the cortical circuit and reduce the propagation of learning-relevant information, which impair motor learning. 1S8-2 The new candidate of teprenone as a novel antidepressant Narumi Hashikawa-Hobara1，Yuta Utaka1，Masafumi Kayano2，Yoshito Zamami2，Naoya Hashikawa1 1Dept. Life Sci., Okayama Univ. of Sci.，2Dept. Clin. Pharmacol. and Therap. Insti. of Biomedical Sci. Grad. Sch., Tokushima Univ. Heat shock proteins (HSPs) are stress-induced chaperones that are involved in neurological disease. Although, increasingly implicated in behavioral disorders and HSPs, the mechanism of action of HSP and its functionally relevant pathway is still unclear. In the present study, we examined whether oral geranylgeranylacetone (GGA), a known HSP inducer, administration induced an anti-depressant effect in a social defeat stress model of depression in mice. We also investigated the possible molecular mechanisms involved, particularly focusing on hippocampal neurogenesis and neurotrophic factor expression. Furthermore, we evaluated the association of teprenone (pharmaceutical name of GGA) use and drug-induced depression using the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS), a large and useful database of adverse events. In stressed mice, hippocampal HSP105 expression decreased. However, administration of geranylgeranylacetone (GGA), a known HSP inducer, increased HSP105 expression and improved depression-like behavior, hippocampal cell proliferation, and elevated brain-derived neurotrophic factor (BDNF) mRNA levels in the mouse hippocampus. Co-treatment with GGA and the BDNF receptor inhibitor K252a suppressed the anti-depressant effects of GGA. HSP105 mRNA knockdown decreased BDNF mRNA levels in HT22 hippocampal cell lines and hippocampal tissue, and inhibited the GGA-mediated anti-depressant effect. Clinical database studies have also suggested that concurrent use of GGA may act against the onset of depressive events following interferon administration. These observations suggest that GGA administration is a therapeutic candidate for depressive diseases by increasing hippocampal BDNF levels via HSP105 expression. 1S8-3 Animal Models of Neuropsychiatric Disorders Tetsushi Sadakata Office for Promotion of the Tenure Track System, Gunma Univ Ca2+-dependent activator protein for secretion 2 (CAPS2) potently promotes the release of brain-derived neurotrophic factor (BDNF). A rare splicing form of CAPS2 with deletion of exon3 (dex3) was identified to be overrepresented in some patients with autism. We generated Caps2-dex3 mice and verified a severe impairment in axonal Caps2-dex3 localization, contributing to a reduction in BDNF release from axons. In addition, circuit connectivity, measured by spine and interneuron density, was diminished globally. The collective effect of reduced axonal BDNF release during development was a striking and selective repertoire of deficits in social- and anxiety-related behaviors.On the other hand, genome-wide association studies of autism have identified several microdeletions due to copy number variation (CNV) in one of the chromosome 7q31.32 alleles on which the locus for CAPS2 is located in autistic patients. To evaluate the biological significance of reducing CAPS2 copy number, we analyzed CAPS2 heterozygous mice. Our present findings suggest that adequate levels of CAPS2 protein are critical for normal brain development and behavior. 1S8-4 Microglia disrupt synapse E/I balance after febrile seizures Ryuta Koyama，Yuji Ikegaya Lab. Chem. Pharmacol., Grad. Sch. Pharmaceut. Sci., Univ. Tokyo Fever (typically greater than 38 ºC)-induced febrile seizures are the most common type of seizures in early childhood. Prolonged febrile seizures could afterwards initiate the development of epilepsy; however, the cellular and molecular links between febrile seizures and epilepsy remain unclear. Here we report that microglia, the brain-resident immune cells, disrupt the excitatory versus inhibitory balance (E/I balance) of synapses in dentate circuits. Microglia detected the increase in brain temperature during experimental febrile seizures through activation of transient receptor potential vanilloid 4 (TRPV4). The TRPV4-mediated Ca2+-influx induced microglial expression of the complement receptor CR3, which is required for complement-mediated synapse elimination by microglia. The activated microglia were attracted to axonal boutons of inhibitory neurons in an activity-dependent manner and preferentially engulfed inhibitory synapses, decreasing the density of inhibitory synapses in the dentate gyrus. Finally, minocycline, an inhibitor of microglial activation, decreased the delayed seizure severity after febrile seizures. Thus, our study provides a novel mechanism by which the brain hyperthermia impairs the synapse E/I balance via activation of microglia.