Transcriptional and behavioral interaction between 22q11.2 orthologs modulates schizophrenia-related phenotypes in mice
Transcriptional and behavioral interaction between 22q11.2 orthologs modulates schizophrenia-related phenotypes in mice
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DOI：
10.1038/nn1562
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发表时间：
2005-11-01
影响因子：
25
通讯作者：
Gogos, JA
中科院分区：
文献类型：
--
作者：
Paterlini, M;Zakharenko, SS;Gogos, JA
22q11.2的微缺失是精神分裂症已知的最高遗传风险因素之一。很可能不止一个基因导致与该位点相关的显著风险。两个候选风险基因编码脯氨酸脱氢酶（PRODH）和儿茶酚-O-甲基转移酶（COMT），分别调节假定的神经调节剂（L-脯氨酸）和神经递质多巴胺的水平。模拟精神分裂症患者中观察到的PRODH缺陷状态的小鼠显示谷氨酸能突触处神经递质释放增加，以及联想学习和对拟精神药物反应的缺陷。转录分析和药理学操作确定了一个转录和行为之间的相互作用，可能是代表一个稳态反应，以增强多巴胺能信号在额叶皮层的BMPH和Comt基因。这种相互作用调节了许多精神分裂症相关的表型，为理解与该基因座相关的高疾病风险、表型的表达或两者提供了框架。
Microdeletions of 22q11.2 represent one of the highest known genetic risk factors for schizophrenia. It is likely that more than one gene contributes to the marked risk associated with this locus. Two of the candidate risk genes encode the enzymes proline dehydrogenase (PRODH) and catechol-O-methyltransferase (COMT), which modulate the levels of a putative neuromodulator (L-proline) and the neurotransmitter dopamine, respectively. Mice that model the state of PRODH deficiency observed in humans with schizophrenia show increased neurotransmitter release at glutamatergic synapses as well as deficits in associative learning and response to psychomimetic drugs. Transcriptional profiling and pharmacological manipulations identified a transcriptional and behavioral interaction between the Prodh and Comt genes that is likely to represent a homeostatic response to enhanced dopaminergic signaling in the frontal cortex. This interaction modulates a number of schizophrenia-related phenotypes, providing a framework for understanding the high disease risk associated with this locus, the expression of the phenotype, or both.