Symposium

Symposium 12 Co-sponsored by Scientific Research on Innovative Areas “Brain and Individuality” Development, Function and Pathology of the nervous system シンポジウム12 神経系の発生・機能とその破綻

SY12-1 Uncovering the mechanisms underlying cortical folding using ferrets フェレットを用いた大脳皮質の脳回形成機構の解析 Kawasaki Hiroshi（河崎洋志） Dept of Med Neurosci, Sch of Medicine, Kanazawa Univ Folds of the cerebral cortex, which are called the gyri and the sulci, are one of the most prominent features of the mammalian brain. To investigate the mechanisms underlying development of cortical folds, we recently developed a genetic manipulation technique for the cerebral cortex of ferrets using in utero electroporation. Genes-of-interest can be expressed in the ferret cortex rapidly and efficiently. We also demonstrated that genes-of-interest can be knocked out in the ferret cortex by combining in utero electroporation and the CRISPR/Cas9 system. Using our technique, we uncovered that FGF signaling is necessary and sufficient for cortical folding. We found that overexpression of FGF induced additional gyri, and that suppression of FGF signaling inhibited cortical folding. In addition, we found that the thickness of upper layers was preferentially affected by FGF signaling, raising the possibility that upper layers are important for cortical folding. Consistently, when radial migration of upper-layer neurons was suppressed by inhibiting Cdk5, cortical folding was inhibited. Our findings provide in vivo data about the mechanisms of cortical folding in gyrencephalic mammals. Our technique for the ferret cerebral cortex is useful for investigating the mechanisms underlying development and diseases related to brain structures of higher mammals.		SY12-2 The role of AUTS2 in synaptic organization and the cognitive functions during postnatal brain development 発達期脳におけるシナプス形成および脳高次機能獲得に関わるAUTS2の生理機能解析 Hori Kei（堀啓）¹，永井拓²，Wei Shan²，山田光代¹，白石玲花¹，菅野康太³，坂本亜沙美¹，阿部学⁴，崎村健司⁴，山田清文²，星野幹雄¹ ¹Dept. Biochem. & Cell Biol., National Inst of Neurosci., NCNP, Japan ²Dept of Neuropsychopharmacology and Hospital Pharmacy, Nagoya Univ. Grad Sch of Med. ³Faculty of Low, Economics & Humanities, Kagoshima Univ. ⁴Dept of Cell Neurobiol, Brain Res Inst, Niigata Univ Autism susceptibility candidate 2 (AUTS2) has been implicated as the gene associated with various psychiatric disorders such as autism spectrum disorders (ASDs), intellectual disabilities (ID) and schizophrenia. In mouse developing CNS, AUTS2 is highly expressed at several brain regions such as cerebral cortex and hippocampus. We have previously demonstrated that cytoplasmic AUTS2 regulated the neuronal migration and neurite formation in the developing cerebral cortex. Furthermore, nuclear AUTS2 has been reported to be involved in the transcriptional regulation of multiple genes for neural development by interacting with the Polycomb group protein complex 1 (PRC1). However, there remain many questions about the physiological roles for AUTS2 in the postnatal brain development. In this study, we conducted a battery of behavioral analyses on two different types of Auts2 mutant mice to examine the involvement of Auts2 in adult cognitive brain functions. Auts2-deficient mice displayed several behavioral abnormalities including a lower anxiety, defects of memory formation as well as social behavior and PPI. Furthermore, the USV analysis exhibited that loss of Auts2 resulted in defects of vocal communications for the adult male mice. We also observed the increased dendritic spines of pyramidal neurons at several brain regions in Auts2 mutant mice, including the Hippocampal CA1, the upper-layer of mPFC and auditory cortex. The Auts2-deleted cultured hippocampal neurons also showed the excess dendritic spine formation in vitro, suggesting that AUTS2 postsynaptically regulates the number of the excitatory synapses. Together, our findings indicate that AUTS2 is critical for the postnatal cortical development to acquire the neurocognitive functions.

SY12-3 Analysis of stress-induced central-peripheral interactions based on individual differences 個体差を考慮した精神的ストレスにおける中枢末梢連関の解析 Sasaki Takuya（佐々木拓哉）^1,2 ¹Lab. Chem. Pharmacol., Grad. Sch. Pharm., Univ. of Tokyo ²PRESTO, JST, Japan Animals show large individual differences in peripheral activity in response to mental stress episodes. Peripheral organ functions such as cardiovascular and respiratory activity are controlled by the autonomic nervous system, which is determined by how the brain outputs to the autonomic nervous system against external conditions. This raises a hypothesis that the individual differences in stress susceptibility might be explained by individual differences in brain activity. It remains, however, largely unknown how the central nervous system and peripheral organs interact with each other. To address this issue, we developed a recording method that comprehensively monitors electrical biosignals representing cardiac rhythm, breathing rhythm, awake/sleep-related muscle contraction, and collective neuronal activity of multiple brain regions. Using this novel technique, we examined physiological changes of cortical and cardiac activity in rats that were subject to social defeat stress. In stress-susceptible rats that were defined based on a significant decrease in heartbeat rates, the power of cortical local field potentials was reduced, so-called small-amplitude irregular activity. These prominent decreases in the local filed potential power occurred at the same time across multiple brain regions, including the hippocampus, the somatosensory cortex, and the thalamus. Such dynamic changes in cortical activity is a possible mechanism to cause abnormal activity of the peripheral organs in response to mental stress episodes.		SY12-4 How paternal aging affects neural development of the offspring: an epigenetic model for neurodevelopment disorders 父加齢はどのように次世代の神経発生に影響するのか：発達障害のエピジェネティックモデルとして Osumi Noriko（大隅典子） Dept. of Developmental Neuroscience, Tohoku University School of Medicine Human epidemiological studies have indicated that paternal age has deleterious impacts on risk in offspring for various mental illnesses such as schizophrenia and autism spectrum disorders. Although de novo genetic mutations and epigenetic changes in aged sperm are assumed to be the underlying mechanisms,the precise causes of disorders linked to paternal age are not well known. We have found that F1 offspring of aged fathers showed impairment in pup’s vocalization,sensorimotor gating and spatial learning. Here we analyzed molecular mechanisms underlying behavioral changes due to paternal aging. Since we found reduction of thickness in the neocortex, especially in the deep layer,at postnatal day 6, when vocalization defects were observed, we profiled gene expression of developing brains at embryonic day11.5 (E11.5) and E14.5 by RNA-seq. Gene Set Enrichment Analysis (GSEA) showed in brains of aged-father derived offspring at E14.5, but not in E11.5, enrichment of “Late-fetal genes” and conversely, that of “Early-fetal genes” in those derived from young father. Interestingly, “NRSF/REST motif genes” and “SFARI genes (autism-related)” were found to be highly enriched in the brains derived from aged father. A possible scenario is that paternal aging may induce in the offspring’s brain precocious neurogenesis via dis-regulation of gene expression by NRSF/REST, a pivotal transcription factor for neurogenesis.Our parallel analyses on sperm DNA methylation at the whole genome level also suggest involvement of hypo-methylation in aged sperm and NRSF/REST as a common motif in hypo-methylated regions. Our findings align with the recent epidemic rise in human neurodevelopmental diseases in modern countries, where people are both marrying and having children later in life.