Kuritaらは，非定型抗精神病薬の効果がヒストン脱アセチル化の作用により変動したことを報告しています。本報告によれば，非定型抗精神病薬 (クロザビン，およびリスペリドン) を長期投与したマウスおよびヒトの前頭前皮質では，代謝型グルタミン酸受容体2型 (mGlu2，別名Grm2) の発現の抑制により非定型抗精神病薬の効果が抑制され，さらにmGlu2プロモーター遺伝子のヒストンが脱アセチル化されています。次いで，この前頭前皮質にヒストン脱アセチル化酵素 (HDAC) 阻害剤のSAHAを追加投与するとmGlu2発現抑制が緩解し，非定型抗精神病薬の効果が改善しています。これらのデータから，HDAC2が統合失調症治療の新しいターゲット分子になり得ることを本報告では示しています。（これらの製品は試薬であり，試験・研究用のみにご使用下さい。）
“HDAC2 regulates atypical antipsychotic responses through the modulation of mGlu2 promoter activity”
M. Kurita, T. Holloway, A. Garcia-Bea, A. Kozlenkov, A. K. Friedman, J. L. Moreno, M. Heshmati, S. A. Golden, P. J. Kennedy, N. Takahashi, D. M. Dietz, G. Mocci, A. M. Gabilondo, J. Hanks, A. Umali, L. F. Callado, A. L. Gallitano, R. L. Neve, L. Shen, J. D. Buxbaum, M.-H. Han, E. J. Nestler, J. J. Meana, S. J. Russo, J. Gonzalez-Maeso, Nat. Neurosci. 2012, 15, 1245. DOI: 10.1038/nn.3181
Histone deacetylases (HDACs) compact chromatin structure and repress gene transcription. In schizophrenia, clinical studies demonstrate that HDAC inhibitors are efficacious when given in combination with atypical antipsychotics. However, the molecular mechanism that integrates a better response to antipsychotics with changes in chromatin structure remains unknown. Here we found that chronic atypical antipsychotics downregulated the transcription of metabotropic glutamate 2 receptor (mGlu2, also known as Grm2), an effect that was associated with decreased histone acetylation at its promoter in mouse and human frontal cortex. This epigenetic change occurred in concert with a serotonin 5-HT2A receptor–dependent upregulation and increased binding of HDAC2 to the mGlu2 promoter. Virally mediated overexpression of HDAC2 in frontal cortex decreased mGlu2transcription and its electrophysiological properties, thereby increasing psychosis-like behavior. Conversely, HDAC inhibitors prevented the repressive histone modifications induced at the mGlu2promoter by atypical antipsychotics, and augmented their therapeutic-like effects. These observations support the view of HDAC2 as a promising new target for schizophrenia treatment.
