Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, NY.
Sichuan Provincial Hospital for Women and Children, Chengdu, China.
Schizophr Bull. 2019 Sep 11;45(5):1012-1023. doi: 10.1093/schbul/sby163.
A combination of genetic and environmental risk factors has been considered as the pathogenic cause for mental disorders including schizophrenia. Here, we sought to find out whether the abnormality of the dopamine system, coupled with the exposure to modest stress, is sufficient to trigger the manifestation of schizophrenia-like behaviors. We found that exposing dopamine D4 receptor knockout (D4KO) mice with 1-week restraint stress (2 h/d) induced significant deficits in sensorimotor gating, cognitive processes, social engagement, as well as the elevated exploratory behaviors, which are reminiscent to schizophrenia phenotypes. Electrophysiological studies found that GABAergic transmission was significantly reduced in prefrontal cortical neurons from stressed D4KO mice. Additionally, administration of diazepam, a GABA enhancer, restored GABAergic synaptic responses and ameliorated some behavioral abnormalities in stressed D4KO mice. These results have revealed that the combination of 2 key genetic and environmental susceptibility factors, dopamine dysfunction and stress, is a crucial trigger for schizophrenia-like phenotypes, and GABA system in the prefrontal cortex is a downstream convergent target that mediates some behavioral outcomes.
遗传和环境风险因素的结合被认为是导致精神障碍（包括精神分裂症）的致病原因。在这里，我们试图找出多巴胺系统的异常，加上适度的压力暴露，是否足以引发类似精神分裂症的行为表现。我们发现，暴露于多巴胺 D4 受体敲除（D4KO）小鼠 1 周的束缚应激（每天 2 小时）可导致感觉运动门控、认知过程、社会参与以及升高的探索行为显著缺陷，这类似于精神分裂症表型。电生理研究发现，应激 D4KO 小鼠前额皮质神经元中的 GABA 能传递显著减少。此外，给予苯二氮䓬类药物，GABA 增强剂，可恢复应激 D4KO 小鼠的 GABA 能突触反应，并改善一些行为异常。这些结果表明，2 个关键的遗传和环境易感性因素（多巴胺功能障碍和应激）的结合是引发类似精神分裂症表型的关键触发因素，而前额叶皮层中的 GABA 系统是介导一些行为结果的下游会聚靶点。
