Schizophrenia and Endocannabinoid Effects on Inhibitory Circuitry

描述（由申请人提供）：精神分裂症患者或有精神分裂症风险的个人使用大麻越来越被认为是一个主要的公共卫生问题。例如，大麻的使用与患精神分裂症的风险增加以及已经患有精神分裂症的人的长期结果较差有关。大麻的使用还引起与前额叶皮层（PFC）相关的认知障碍，类似于精神分裂症中所见的认知障碍。有趣的是，RFC GABA神经元的缺陷可能导致精神分裂症的认知问题，大麻通过激活CB 1受体减少GABA信号传导。因此，大麻使用和精神分裂症认知障碍之间的一个潜在联系可能涉及RFC GABA系统中缺陷的相互作用。对精神分裂症患者eCB系统的直接调查可能有助于进一步澄清精神分裂症患者使用大麻的负面后果的生物学基础。例如，确定最近报道的精神分裂症中RFC CB 1受体水平较低的发现是否反映了eCB信号传导的缺陷，或者相反，CB 1受体水平响应于过度的eCB信号传导而下调，需要了解与CB 1受体结合的eCB配体（2-AG）。此外，为什么eCB系统首先在精神分裂症中发生改变？一种可能性是，在eCB信号的改变在精神分裂症的发病下游GABA synthesis.Therefore，前两个目标将确定是否（以及如何）的mRNA和蛋白质水平的合成和代谢酶（甘油二酯脂肪酶和甘油单酯脂肪酶）2-AG的RFC在精神分裂症中使用定量PCR，原位杂交，蛋白质印迹和免疫细胞化学改变。第三个目标将使用体内注射表达针对GABA合成酶GAD 67的siRNA的慢病毒载体，并确定对eCB信号传导标志物的影响。该应用程序的培训目标是获得必要的研究技能，成为一名独立的调查员，通过将死后人脑组织研究与动物模型中的细胞类型特异性遗传操作相结合，测试涉及精神分裂症皮质回路异常的发病假设。公共卫生相关性：这些研究将为精神分裂症患者大脑自身大麻系统的潜在异常提供深入了解，并可能有助于确定该疾病的新治疗可能性。

DESCRIPTION (provided by applicant): Cannabis use by individuals with, or at risk for, schizophrenia is increasingly recognized as a major public health concern. For example, cannabis use is linked to an increased risk for developing schizophrenia and poorer long-term outcomes in individuals who already have schizophrenia. Cannabis use also induces prefrontal cortex (PFC)-related cognitive impairments similar to those seen in schizophrenia. Interestingly, deficits in RFC GABA neurons may lead to cognitive problems in schizophrenia, and cannabis reduces GABA signaling by activating the CB1 receptor. Thus, one potential link between cannabis use and cognitive impairments in schizophrenia may involve an interaction of deficits in the RFC GABA system. Direct investigations of the eCB system in schizophrenia may help further clarify the biological basis for the negative consequences of cannabis use in schizophrenia. For example, determining whether the recently reported finding of lower RFC CB1 receptor levels in schizophrenia reflects a deficiency in eCB signaling, or, conversely, a downregulation of CB1 receptor levels in response to excessive eCB signaling requires knowledge of the eCB ligand (2-AG) that binds to the CB1 receptor. Furthermore, why is the eCB system altered in schizophrenia in the first place? One possibility is that alterations in eCB signaling in schizophrenia are pathogenetically downstream to impairments in GABA synthesis.Therefore, the first two aims will determine whether (and how) the mRNA and protein levels for the synthesizing and metabolizing enzymes (diacylglycerol lipase and monoglyceride lipase) for 2-AG are changed in the RFC in schizophrenia using quantitative PCR, in situ hybridization, Western blots, and immunocytochemistry. The third aim will use in vivo injections of lentiviral vectors expressing siRNA against the GABA synthesizing enzyme, GAD67, and determine the effects on markers of eCB signaling. The training goal of this application is to obtain the necessary research skills to become an independent investigator who tests pathogenetic hypotheses involving cortical circuitry abnormalities in schizophrenia by combining postmortem human brain tissue studies with cell-type specific genetic manipulations in animal models. PUBLIC HEALTH RELEVANCE: These studies will provide insight into potential abnormalities in the brain's own cannabis system in schizophrenia and may help identify new treatment possibilities for the disease.