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鉴定了许多在大脑皮层中改变表达的转录物，特别是那些参与GABA能和多巴胺能神经传递的转录物。这个提议的目标是将这些发现牢固地置于听觉感觉皮层中已识别的神经回路的背景下。将通过定制设计的阵列分析评价单细胞基因表达，以比较被认为参与精神分裂症发病机制的不同神经元群体中多种转录物（>570）的表达。这些实验将确定基因表达途径以及具有改变的表达的特定转录物，并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改变的基因表达是否1）伴随着个体细胞类型的相对密度的降低，或2）反映完整神经元群体内的基因表达改变。这两种情况导致了关于精神分裂症基因表达改变原因的不同结论。这些数据将进一步加深我们对精神分裂症病因学的理解，并为指导精神分裂症的药物治疗策略提供电路相关的模型。公共卫生相关性目前的证据表明，在精神分裂症中，大脑皮层中抑制性神经元的特定子集可能缺失或功能中断。这项建议将集中在这些神经元的几个亚型，特别是怀疑参与精神分裂症的发病机制。它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尸检样本中确定。这一发现将有助于确定精神分裂症大脑皮层病理学的确切性质。

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.