行動および神経疾患の分子機構
Molecular basis of behavior and neurological disorders
O1-7-6-1
マウス自発行動及び不安様行動における睡眠剥奪ストレスとヒスタミンの効果について
Low histamine diet increases anxiogenic like behavior in chronic sleep deprived mice

吉川雄朗1, 谷内一彦1
○Attayeb Mohsen1, Takeo Yoshikawa1, Kazuhiko Yanai1
Department of Pharmacology, Tohoku University1

Histamine is abundant in the mammalian brain and functioning as a monoamine neurotransmitter. It is well known that H1 receptor blockers are sedatives, while H3 receptor antagonists promote wakefulness. This study examined the effects of acute and chronic sleep deprivation on animal behaviors and brain histamine neurochemistry. We first examined the histamine turnover rate in C 57/6J black male mice after 24 hours of sleep deprivation using HPLC. We also measured the expression of histamine related genes such as histamine receptors, histamine production and metabolism enzymes. Histamine turnover rate increased in the cortex, hippocampus and midbrain. H3 receptor expression increased significantly in the hippocampus. For further evaluation of chronic sleep deprivation, we examined the behaviors of mice during one month of 20 h ours daily sleep deprivation and/or low histamine diet. This experiment designed to test two factors, sleep deprivation and dietary histamine. C57/6J black male mice were sleep-deprived using a forced exercise method with rolling wheels and given low or normal histamine diet. Two-way ANOVA analyses showed that low histamine diet increased anxiogenic behavior in the sleep-deprived mice.
O1-7-6-2
Protocadherin alpha (PCDHA) as a novel susceptibility gene for autism
○Anitha Ayyappan1, Ismail Thanseem2, Kazuhiko Nakamura3, Kazuo Yamada4, Yoshimi Iwayama4, Tomoko Toyota4, Katsuaki Suzuki1, Toshiro Sugiyama5, Masatsugu Tsujii1,6, Takeo Yoshikawa4, Norio Mori1,2
Hamamatsu University School of Medicine1, Dept of Psychiatry and Neurology, Hamamatsu Univ Sch Med, Hamamatsu, Japan2, Dept of Psychiatry, Hirosaki Univ Sch Med, Hirosaki, Japan3, Lab for Molecular Psychiatry, RIKEN Brain Sci Institute, Wako, Japan4, Dept of Child and Adolescent Psychiatry, Hamamatsu Univ Sch Med, Hamamatsu, Japan5, Faculty of Sociology, Chukyo Univ, Toyota, Japan6

Synaptic dysfunction has been shown to be involved in the pathogenesis of autism. We hypothesize that protocadherin alpha gene cluster (PCDHA), involved in synaptic specificity and in serotonergic innervation of brain, could be a suitable candidate gene for autism. 14 PCDHA SNPs were examined for genetic association with autism in DNA samples of 3211 individuals (841 families, including 574 multiplex families) obtained from AGRE. Five SNPs (rs251379, rs1119032, rs17119271 rs155806, rs17119346) showed significant associations with autism. Strongest association (p=0.0006) was observed for rs1119032 (Z-score of risk allele G=3.415) in multiplex families. SNP associations withstand multiple testing correction in multiplex families (p=0.041). Haplotypes involving rs1119032 showed very strong association, withstanding multiple testing correction, with autism. In quantitative transmission disequilibrium test (QTDT) of multiplex families, the G allele of rs1119032 showed a significant association (p=0.033) with ADI-R_D scores (early developmental abnormalities). We also found a significant difference in the distribution of ADI-R_A scores (social interaction) between the A/A, A/G and G/G genotypes of rs17119346 (p=0.0025). Our study provides strong genetic evidence of PCDHA as a potential candidate gene for autism.
O1-7-6-3
An autism-linked mutation in neuroligin-3 affects development of climbing fiber to Purkinje cell synapses in the cerebellum
○Esther Suk King Lai1, Hisako Nakayama2, Takanobu Nakazawa1, Katsuhiko Tabuchi3, Kouichi Hashimoto2, Masanobu Kano1
Dept Neurophysiol, Grad Sch Med, University of Tokyo, Tokyo, Japan1, Depart Neurophysiol, Grad Sch Biomed Sci, Hiroshima University2

Neuroligin, a postsynaptic cell-adhesion molecule, is involved in the formation and maturation of synapses by interacting with presynaptic neurexin. Mutations in neuroligin genes, including the arginine to cystein substitution at the 451th amino acid (R451C) of neuroligin-3 (NLGN3), have been identified in patients with autism spectrum disorders (ASDs). Previous studies including post-mortem studies in autistic patients and morphological examinations in ASD mouse models have implicated the cerebellar dysfunction and Purkinje cell (PC) loss in ASDs. In the present work, we investigated possible associations between R451C mutation in NLGN3 and synaptic development and function in the cerebellum. In NLGN3 R451C knock-in mice, elimination of redundant climbing fiber (CF) to PC synapses was impaired from postnatal day 11 to 14 (P11 to 14), but a majority of PCs in NLGN3-R451C mice became mono-innervated as in wild-type mice after P15. In addition, strengthening of a single CF among multiple CFs in each PC (functional differentiation) was almost normal up to around P20, but was found to be significantly impaired in adulthood in NLGN3-R451C mice. Furthermore, inhibitory synaptic transmission to PCs was enhanced, while the amplitude and frequency of miniature EPSCs and the probability of neurotransmitter release were normal, in NLGN3-R451C mice. These results suggest that a single point mutation in NLGN3 significantly influences the synapse development and refinement in cerebellar circuitry which might be related to the pathogenesis of human ASDs.
O1-7-6-4
匂い物質-受容体ペアの網羅的スクリーニングによって明らかになった匂いの濃度に依存した嗅覚受容体の使い分け
Screening of odor-receptor pairs reveals concentration-dependent switches in olfactory receptors

○魚住隆行1, 谷口群1, 桐山恵介1, 紙崎智子2, 広津崇亮1,2
○Takayuki Uozumi1, Gun Taniguchi1, Keisuke Kiriyama1, Tomoko Kamizaki2, Takaaki Hirotsu1,2
九大院・システム生命科学1, 九大院・理・生物2
Grad Sch. of Sys Life Sci., Kyushu Univ., Fukuoka, Japan1, Dept. of Biol. Grad Sch. of Sci., Kyushu Univ., Fukuoka, Japan2

The olfactory system plays important roles for various behaviors. To totally understand this system, it is important to know the relationship between olfactory receptors and odorants. However correspondences between ligands and receptors remain unknown. Also in C. elegans, one odor-receptor pair has been identified; diacetyl and ODR-10. Therefore, we carried out systematic screens to identify olfactory receptors for specific odorants in C. elegans. Functions of each of 822 putative olfactory receptor genes were inhibited with feeding RNA interference and responses of RNAi-treated animals to 11 odorants were tested. After the third screening, we found that RNAi of 194 genes caused weaker responses to one or more odorants and we obtained candidate genes for all of the 11 odorants. Among them, SRI-14 has been obtained for a candidate receptor for high concentrations of diacetyl. sri-14 mutants showed defects in avoidance of high concentrations of diacetyl, but not in attraction to low concentrations of the odorant. Expression of sri-14 gene was observed in ASH and AWC sensory neurons, and ASH-specific sri-14 RNAi caused defects in avoidance of high concentrations of diacetyl.Finally, we demonstrated calcium imaging in several sensory neurons responding to high or low concentrations of diacetyl. AWA neurons which express diacetyl receptor, ODR-10 responded to both high and low concentrations of diacetyl, whereas ASH neurons responded only to high concentrations. odr-10 mutant showed normal response of ASH and weak response of AWA after application of low concentrations of diacetyl; however, sri-14 mutant showed weak ASH calcium responses after application of high diacetyl concentrations. Furthermore, ASH-specific sri-14 RNAi caused reduced calcium responses of ASH to high concentration of diacetyl.These results suggest that SRI-14 functions in ASH neurons as an OR for high concentrations of diacetyl, whereas ODR-10 functions in AWA as an OR for low concentrations.
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