Hint-/-小鼠精神分裂样表型筛选及其VTA-NAc-PFC通路神经可塑性机制研究

Schizophrenia is a debilitating psychotic disorder, the underlying mechanisms of which remain poorly defined. Neuroplasticity has been proposed as a core pathogenic mechanism underlying the occurrence and development of schizophrenia. Previous studies demonstrated that the histidine triad nucleotide-binding protein-1 (HINT1) gene which locates on human chromosome 5q31.2 is associated with schizophrenia. In our preliminary studies, we showed that Hint1 gene knockout (KO) mouse could constitute an appropriate genetic model for schizophrenic research, indicating a prominent and functionally important role of HINT1 in schizophrenia. Therefore, the specific aims of this proposal are to: （1) determine the phynotype and/or endophynotype of schizophrenia that developed in Hint1 KO mice; 2) identify the relevant neuroplasticity changes in VTA-NAc-PFC neural circuit. The aims of this proposal will be tested using integrated phynotype and endophynotype of schizophrenia selection approaches in Hint1 KO mice, and we will then further explore the underlying neuroplasticity mechanisms of which in the VTA-NAc-PFC neurocircuit. The long term goal of the proposed studies is to further our understanding the pathogenesis of schizophrenia with the hope of this leads to new therapies for schizophrenia.

精神分裂症是一种病因不明的致残性精神疾病，神经可塑性机制在精神分裂症的发病中居于核心地位。以往的研究发现三联组氨酸核苷酸结合蛋白1（Histidine triad nucleotide binding protein 1, HINT1）基因是精神分裂症易感基因；我们的研究则表明：HINT1基因敲除小鼠可能是一种精神分裂症遗传模型。据此，本研究旨在阐明（1）HINT1基因KO小鼠表征着精神分裂症遗传模型哪些表型/内表型？（2）这些表型和内表型的VTA-NAc-PFC通路的神经可塑性机制是什么？本研究拟利用HINT1基因KO小鼠，系统筛选其精神分裂样行为表型/内表型（感觉运动门控、认知缺陷、阳性、阴性、情感性症状），并对其VTA-NAc-PFC通路的神经可塑性机制（突触形态、突触效能、突触可塑性相关分子表达、信号传导、表观遗传调控等）进行考察，以期为精神分裂症发病机制和新药开发提供有益的启示。

精神分裂症是一种病因不明的精神疾病，以往的研究发现三联组氨酸核苷酸结合蛋白1（Histidine triad nucleotide binding protein 1, HINT1）基因是精神分裂症易感基因。然而，目前国内外对于HINT1与精神分裂症的关系及具体机制的研究相对较少。本项目运用HINT1敲除小鼠，系统筛选了其精神分裂样行为表型/内表型（包括感觉运动门控、认知缺陷、阳性、阴性、情感性症状等）。同时考察了HINT1敲除小鼠多个脑区，包括前额叶皮质(prefrontal cortex, PFC)、伏隔核(nucleus accumbens, NAc)、海马(hippocampus, HIP)内精神分裂症相关分子的差异。已得到的结果表明：HINT1基因敲除小鼠确实表现出若干精神分裂样的行为异常，如感觉运动门控失调，攻击行为增加，社会退缩等。并且发现，敲除小鼠的NAc脑区存在NMDA功能不足。我们的研究发现有望为精神分裂症发病机制和新药开发提供有益的启示