Schizophrenia and Endocannabinoid Effects on Inhibitory Circuitry

描述（由申请人提供）：精神分裂症患者或有患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预后较差有关。大麻的使用也会引起与前额叶皮层（PFC）相关的认知障碍，类似于精神分裂症。有趣的是，RFC GABA神经元的缺陷可能导致精神分裂症患者的认知问题，而大麻通过激活CB1受体来减少GABA信号。因此，大麻使用与精神分裂症患者认知障碍之间的潜在联系可能涉及RFC - GABA系统缺陷的相互作用。直接调查精神分裂症中的eCB系统可能有助于进一步阐明大麻使用在精神分裂症中的负面影响的生物学基础。例如，确定最近报道的精神分裂症患者RFC CB1受体水平较低的发现是否反映了eCB信号的缺乏，或者相反，CB1受体水平的下调是对过量eCB信号的反应，需要了解与CB1受体结合的eCB配体（2-AG）。此外，为什么欧洲央行体系一开始就发生了精神分裂？一种可能性是精神分裂症中eCB信号的改变在病理上是GABA合成损伤的下游。因此，前两个目标将通过定量PCR、原位杂交、Western blots和免疫细胞化学来确定精神分裂症RFC中2-AG合成和代谢酶（二酰基甘油脂肪酶和单甘油酯脂肪酶）的mRNA和蛋白质水平是否（以及如何）发生变化。第三个目标是在体内注射表达siRNA的慢病毒载体，对抗GABA合成酶GAD67，并确定对eCB信号标记物的影响。该应用程序的培训目标是获得必要的研究技能，成为一名独立的研究者，通过将死后人类脑组织研究与动物模型中的细胞类型特定遗传操作相结合，来测试涉及精神分裂症皮层电路异常的发病假设。公共卫生相关性：这些研究将深入了解精神分裂症患者大脑自身大麻系统的潜在异常，并可能有助于确定这种疾病的新治疗方法。

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.