演題番号 : P1-p08
吉川 武男 / Takeo Yoshikawa:1 前川 素子 / Motoko Maekawa:1 大西 哲生 / Tetsuo Ohnishi:1 橋本 謙二 / Kenji Hashimoto:2 渡邉 明子 / Akiko Watanabe:1 岩山 佳美 / Yoshimi Iwayama:1 大羽 尚子 / Hisako Ohba:1 服部 栄治 / Eiji Hattori:1 山田 和男 / Kazuo Yamada:1
1:独立行政法人理化学研究所脳科学総合研究センター 分子精神科学研究チーム / Laboratory for Molecular Psychiatry, RIKEN Brain Science Institue 2:千葉大学社会精神保健教育研究センタ－・病態解析研究部門 / Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan
Deficits in prepulse inhibition (PPI) are known in mental illnesses, including schizophrenia. NMDA receptor function affects PPI integrity and D-serine and glycine are endogenous co-agonists for the receptor. Our previous quantitative trait loci (QTL) analysis using C57BL/6 (B6) mice with better PPI performance and C3H/He (C3) with lower PPI score, shows that genes for both D-serine and glycine synthesizing enzymes (Srr and Shmt1, respectively) are located in the same PPI-QTL peak. Therefore, we set out to determine which gene is likely to explain the PPI difference and whether the gene is relevant to schizophrenia. We firstly examined brain interstitial fluid levels of the two amino acids in B6 and C3, using microdialysis. Next, we analyzed expression levels and genetic polymorphisms of the two genes. Finally, we evaluated expression levels of the two genes in the postmortem brains of schizophrenia and genetic associations with the disease (1,060 cases and 1,060 controls). Recovery of D-serine and glycine from the dialysate was higher in B6, compared to C3. There were promoter polymorphisms in Shmt1, which elicit lower transcriptional activity in B6 compared to C3, but no such in Srr. Human studies revealed higher expression levels of SHMT1 in the postmortem brains from schizophrenics compared to controls, but no changes in SRR levels. Genetic analysis detected a nominal association between SHMT1 and schizophrenia. These results suggest that Shmt1 (SHMT1) is likely to be one of the genetic components regulating PPI in mice and relevant to schizophrenia in humans.