自閉症　基礎 Autism: Basic
O2-9-3-1 自閉症モデルラットにおける小脳のPurkinje細胞数の減少 Reduction of cerebellar Purkinje cells in the thalidomide-induced autism model rats ○大河原剛1, 江藤みちる1, 成田正明1 ○Takeshi Ohkawara1, Michiru Ida-Eto1, Masaaki Narita1 三重大学大学院　医学系研究科　発生再生医学1 Department of Developmental and Regenerative Medicine, Mie University, Tsu, Japan1 Introduction: We have created autism model rats by administration of thalidomide on embryonic day (E) 9, which corresponds human E20-24. These rats mimic to human autism in terms of behaviorally and biochemically (Narita N et al., Pediatr Res. 2002; Miyazaki K et al., Int J Dev Neurosci. 2005; Narita M et al., Neurosci Res. 2010; Tashiro Y et al., Int J Dev Neurosci. 2011; Oyabu A et al., Int J Dev Neurosci. in press). Cerebellar dysfunctions such as clumsiness are known to be accompanied in autistic patients. However, molecular mechanisms regarding cerebellar dysfunction in autism have not been known. In the present study, we assessed cerebellar Purkinje cells in autism model rats compared to control rats. Methods: Thalidomide-induced autism model rats were made as reported previously (Narita N et al., Pediatr Res. 2002). The linear density of Purkinje cells following immunostaining with anti-calbindin antibody at postnatal 50-53 was assessed, which was determined by measuring the length of a line along with Purkinje cell layer and counting the number of Purkinje cells along this line, and compared with controls. Results: The linear density of Purkinje cells were significantly decreased in autism model rats (n=10) compared to control rats (n=10) (18.12 cells/mm vs 20.57 cells/mm, p<1.0E-06, t-test). Discussion: This result indicates that maternal exposure to thalidomide causes, in addition to behavioral, biochemical, and morphological abnormalities, cerebellar impairments to offspring in the adult. This result may thus give some explanations in the mechanism of clumsiness in autism.	O2-9-3-2 脳発達障害に関わることが期待される新規遺伝子の解析 Study of new candidate genes critical for human developmental disorders ○小泉惠太1, 中尾啓子2, 中島日出夫3 ○Keita Koizumi1, Keiko Nakao2, Hideo Nakajima3 金沢大学　子どものこころの発達研究センター1, 埼玉医大・生理学2, 熊大・エイズ学研究センター3 Center for Child Mental Dev. Kanazawa Univ, Kanazawa1, Dept. of Phys., Saitama Med. Univ, Moroyama2, Center for AIDS Res., Kumamoto Univ.3 Numbers of studies indicate human developmental disorders such as autism and mental retardation are mainly caused by genes minor dysfunctions. However, little is known about genes networks that cause neural dysfunction in cognitive development during childhood. We have been trying to identify new candidates critical for human developmental disorders by screening Drosophila and mouse genes involved in neural development. Here we show new candidates, Fam107A/B that may have functions to modify actin assembly. A recent work from other group indicates Fam107A is a stress (maternal separation) response gene that alters spine density in hippocampus. Over expression of Fam107A improves cognitive behavior such as spatial memory (Schmidt et al., PNAS, 2011). These data suggest Fam107A may have critical role for human cognitive development. The other gene Fam107B (we call it as "Hit") is a homologous gene that have same functional domain with Fam107B but little is known about its function in nervous system. Using neuron-like cell line, PC12 and mouse neural primary cells, we are studying functions of these genes in vitro. Neurite outgrowth study in both PC12 and primary neurons showed FAM107B inhibits neurite outgrowth by over expression. Transwell assay showed over expression of both FAM107A/B change PC12 cells migration induced by NGF. Co-localization of F-actin and FAM107A or B was observed in outer membrane ruffles after NGF induction. To study in vivo function, we also tried gene transferring of FAM107B in utero that caused cortex migration defects. These data suggest FAM107A/B have similar but independent molecular functions in neurite extension & migration.
O2-9-3-3 CAPS2スプライシング異常による自閉症モデルマウスの解析 Reduced axonal localization of a Caps2 splice variant impairs axonal release of BDNF and causes autistic-like behavior in mice ○定方哲史1 ○Tetsushi Sadakata1 群馬大学　先端科学研究指導者育成ユニット1 Advanced Scientific Research Leaders Development Unit, Gunma University, Gunma1 Ca2+-dependent activator protein for secretion 2 (CAPS2 or CADPS2) 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. Here, 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. Together, these findings represent the first mouse model of a molecular mechanism linking BDNF-mediated coordination of brain development to autism-related behaviors and patient genotype.	O2-9-3-4 自閉症・ADHDなど発達障害の原因と発症メカニズム―農薬、PCBなど神経発達毒性物質によるシナプス形成関連遺伝子発現のかく乱― A causal factor of developmental disorders (autism, ADHD and LD) and their pathogenetic mechanism; Disruption of synaptogenesis-related gene expression by developmental neurotoxic chemicals such as pesticides and PCBs ○黒田洋一郎1, 木村-黒田純子2 ○Yoichiro Kuroda1, Junko Kimura-Kuroda2 環境脳神経科学情報センター1, 東京都医学研、脳発達・神経再生2 Environmental Neurosci. Info. center,Tokyo1, Tokyo Metropolitan Institute of Medical Science,Tokyo,Japan2 Incidence of autism has been increased in recent decades. The cause of increase is obviously not genetic but environmental. Genetic background concerning synaptogenesis for higher functions impaired in such disorders children's brain contributes vulnerability of the disorders. Epidemiological data showed children exposed to organophosphate pesticides having anti-cholinesterase toxicity, appeared to have more risk f of ADHD (Bouchard et al, 2010). Perinatal exposure of an organophosphate insecticide, chlorpyrifos, is suggested to be a causal factor of autism in which cholinergic abnormalities are found in the brain. Thyroid hormone is an essential factor of synaptogenesis to develop neuronal networks which subserve higher functions of the human brain. Polychlorinated biphenyls (PCBs) inhibit thyroid hormone-regulated gene expressions. Hydroxy-PCBs, metabolites of PCBs in the brain also inhibit the extension of dendrites and following synaptogenesis. Maternal plasma PCB levels in cynomolgus monkeys affect infant social skills (Nakagami et al, 2011), which may relate to development of autism. These data, together with other evidence, support a general pathogenetic mechanism of developmental disorders. Perinatal exposure of environmental chemicals (pesticides, PCBs, methylmercury) disrupt gene expression for synaptogenesis spatiotemporally. Therefore, specific vulnerable parts of neural circuits/networks to each agent fail to develop normally, resulting development of disorders impaired specific behaviors. Heterogeneity and co-morbidity of each disordered child's condition is explained by complex interactions of heterogeneous genetic background and spatiotemporally different exposures of multiple environmental neurotoxicants. Some neonicotinoid insecticides showed to disrupt expression of many synaptogenesis-related genes, detected by whole genome gene expression microarray. The data suggest the neonicotinoids are possible causal factor of developmental disorders.

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