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日益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和已经患有精神分裂症的人的长期结果较差有关。大麻的使用也会导致与精神分裂症类似的前额叶皮质(PFC)相关的认知障碍。有趣的是，RFC GABA神经元的缺陷可能会导致精神分裂症的认知问题，而大麻通过激活CB1受体来减少GABA信号。因此，精神分裂症患者使用大麻和认知障碍之间的一个潜在联系可能涉及RFC GABA系统缺陷的相互作用。对精神分裂症患者ECB系统的直接研究可能有助于进一步阐明使用大麻对精神分裂症产生负面后果的生物学基础。例如，要确定最近报道的精神分裂症患者RFC CB1受体水平降低是否反映了ECB信号的缺陷，或者相反，CB1受体水平因过度的ECB信号而下调，需要了解与CB1受体结合的ECB配体(2-AG)。此外，为什么精神分裂症患者的欧洲央行系统一开始就会改变？一种可能性是，精神分裂症患者ECB信号的变化在病理性上顺着GABA合成的障碍而下。因此，前两个目标将通过定量PCR、原位杂交、Western blotts和免疫细胞化学来确定2-AG的合成和代谢酶(二酰甘油脂肪酶和单甘酯脂肪酶)的mRNA和蛋白质水平是否(以及如何)在精神分裂症的RFC中发生变化。第三个目标是在体内注射表达针对GABA合成酶GAD67的siRNA的慢病毒载体，并确定对ECB信号标志的影响。这个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者，通过结合死后人类脑组织研究和动物模型中细胞类型的特定遗传操作来测试涉及精神分裂症皮质回路异常的病因学假说。公共卫生相关性：这些研究将提供对精神分裂症患者大脑自身大麻系统潜在异常的洞察，并可能有助于确定这种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.