Cortical interneuron number and expression profile in schizophrenia

描述（由申请人提供）：精神分裂症的基因表达研究已经确定了一些在大脑皮层中表达改变的转录本，特别是那些涉及gaba能和谷氨酸能神经传递的转录本。这项提议的目的是将这些发现牢固地置于听觉感觉皮层中已确定的神经回路的背景下。单细胞基因表达将通过定制设计的阵列分析来评估，以比较多种转录本（>570）在不同神经元群体中的表达，这些转录本被认为与精神分裂症的发病机制有关。这些实验将确定基因表达途径以及改变表达的特定转录本，同时确定其表达改变的神经元亚型。这些相同神经元群体的体视学测量将确定基因表达的改变是1)伴随着单个细胞类型相对密度的降低，还是2)反映完整神经元群体内基因表达的改变。这两种情况导致了关于精神分裂症基因表达改变的原因的不同结论。这些数据将进一步加深我们对精神分裂症病因的理解，并提供与神经回路相关的模型来指导精神分裂症的药物治疗策略。目前的证据表明，精神分裂症患者大脑皮层中特定的抑制性神经元亚群可能缺失或功能紊乱。这一建议将重点放在这些神经元的几个亚型上，这些亚型尤其被怀疑与精神分裂症的发病机制有关。他们的基因表达谱和相对数量将在精神分裂症和正常大脑的死后样本中确定。这些发现将有助于确定大脑皮层精神分裂症病理的确切性质。

DESCRIPTION (provided by applicant): Gene expression studies in schizophrenia have identified a number of transcripts that have altered expression in the cerebral cortex, especially those involved in GABA-ergic and glutamatergic neurotransmission. The goal of this proposal is to place those findings firmly into the context of identified neural circuits in auditory sensory cortex. Single cell gene expression will be evaluated via custom-designed array analysis to compare the expression of multiple transcripts (>570) in distinct neuronal populations believed to be involved in the pathogenesis of schizophrenia. These experiments will identify gene expression pathways as well as specific transcripts that have altered expression, and simultaneously identify the neuron subtypes in which their expression is altered. Stereological measurements of these same neuron populations will determine whether altered gene expression is 1) accompanied by a decrease in the relative density of individual cells types, or 2) reflect gene expression alterations within intact neuronal populations. These two scenarios lead to different conclusions about the cause of altered gene expression in schizophrenia. These data will further our understanding of the etiology of schizophrenia, and provide circuitry-related models to guide pharmacotherapeutic strategies for the treatment of schizophrenia. PUBLIC HEALTH RELEVANCE Current evidence suggests that specific subsets of inhibitory neurons in the cerebral cortex may be missing, or functionally disrupted in schizophrenia. This proposal will focus on several subtypes of these neurons that are especially suspected to be involved in the pathogenesis of schizophrenia. Their gene expression profile and the relative number will be determined in postmortem samples from schizophrenia and normal brains. The findings will help identify the precise nature of schizophrenia pathology in the cerebral cortex.