Molecular and neuronal pathway-specific analysis of pathognomonic signatures in two-hit schizophrenia mouse models combining environmental and genetic risk factors

越来越多的证据表明，在精神病的病因学，包括精神分裂症（SZ）和双相情感障碍的大脑区域的功能连接紊乱。认知症状是这组异质性疾病的共同标志。然而，基本机制在很大程度上仍然难以捉摸。人类成像数据和动物模型研究表明，腹侧海马（vHi）和内侧前额叶皮质（mPFC）的相互作用受损可能与SZ的认知缺陷有关。在这个建议中，我们建议应用光学生理学的神经元型报告小鼠的脑切片结合分子分析技术来表征vHi-mPFC相互作用的途径特异性机制。因此，我们将利用一个良好表征的SZ风险基因TCF 4的小鼠模型，命名为Tcf 4 tg与内源性大麻素受体阳性中间神经元和小白蛋白阳性中间神经元的荧光报告小鼠杂交，其中可以进行细胞类型特异性光生理记录和分子分析。我们以前可以表明，Tcf 4 tg小鼠显示几种行为内表型的Sz，包括Hi依赖的认知缺陷和感觉运动门控。特别是，依赖于mPFC的认知缺陷被放大时，Tcf 4 tg小鼠进行心理社会压力建模基因x环境（GXE）的相互作用的SZ。如果成功，我们将确定Tcf 4 tg GxE模型中受干扰的vHi-mPFC连接的细胞和分子底物，这将为未来其他模型的后续研究铺平道路。

Increasing evidence suggest that disturbed functional connectivity across brain regions is implicated in the etiology of psychotic diseases, including schizophrenia (SZ) and bipolar disorders. Cognitive symptoms are a common hallmark of this heterogeneous group of diseases. The underlying mechanisms, however, remain still largely elusive. Human imaging data and studies in animal models suggest that impaired interactions of the ventral Hippocampus (vHi) and the medial prefrontal Cortex (mPFC) could be associated with cognitive deficits in SZ. In this proposal, we suggest to apply optophysiology on brain slices of neuron-type reporter mice in combination with molecular profiling techniques to characterize pathway-specific mechanisms underlying vHi-mPFC interactions. Therefore, we will make use of a well characterized mouse model for the SZ-risk gene TCF4 named Tcf4tg crossed with fluorescent reporter mice for endocannabinoid receptor-positive interneurons and parvalbumin-positive interneurons, in which cell-type specific optophysiological recordings and molecular profiling can be performed. We could previously show that Tcf4tg mice display several behavioral endophenotypes of Sz, including Hi dependent cognitive deficits and sensori-motor gating. In particular, cognitive deficits depending on the mPFC are amplified when Tcf4tg mice are subjected to psychosocial stress modeling gene x environment (GxE) interactions of SZ. If successful, we will identify the cellular and molecular substrates underlying disturbed vHi-mPFC connectivity in the Tcf4tg GxE model which would pave the way for follow-up studies in other models in the future.