Deficits in cortical basket cell signaling in schizophrenia

描述（由申请人提供）：精神分裂症是一种使人衰弱的疾病，影响1%的人口，对个人，家庭和社会造成巨大损失。认知能力是精神分裂症患者就业、社会融合和复发的最佳预测因子，但目前的药物治疗并不能解决认知功能障碍。认知的核心组成部分是工作记忆（WM），它依赖于背外侧前额叶皮层（DLPFC）回路的适当激活，并且WM和DLPFC激活在精神分裂症中受损。为了确定改善WM的治疗靶点，必须确定DLPFC电路异常的潜在性质。小清蛋白（PV）篮状细胞突触到锥体细胞的体周区域上，并且对于同步神经群体以在γ范围（30 - 90 Hz）内振荡是至关重要的。伽马振荡被认为是工作记忆能力的基础，精神分裂症患者在工作记忆任务中表现出受损的伽马振荡。最近的证据表明，PV篮状细胞轴突和突触显着减少，如果在发展过程中没有足够的GAD 67水平在精神分裂症DLPFC，GAD 67 mRNA是检测不到的PV中间神经元的45%，这表明这些GAD 67阴性，PV阳性中间神经元形成较少的连接与锥体细胞。因此，PV篮细胞连接的改变可能导致精神分裂症WM受损的电路异常。为了检验PV篮细胞输入在精神分裂症中减少的假设，在来自精神分裂症的DLPFC组织中相对于对照受试者检查突触前和突触后标记物。在目的1中，一种新的共聚焦显微镜方法被用来测试的假设，DLPFC锥体细胞接受较少的PV篮细胞输入精神分裂症。PV篮细胞通过含有α亚基的GABAa受体突触到锥体细胞体信号。因此，在目标2中，使用相同的方法来检验精神分裂症患者锥体细胞膜上α亚基簇的数量较低的假设。最近的证据表明，PV篮细胞输入锥体细胞，但不是中间神经元，是重要的γ ocsillations。因此，在目的3中，使用双标记原位杂交来测试α亚基仅在锥体细胞中较低的假设，以确定精神分裂症中含有α mRNA的锥体细胞和中间神经元的百分比。相关性：精神分裂症影响了超过300万美国人，每年花费620亿美元，认知能力是这些患者就业和康复的最佳预测因素。目前没有改善精神分裂症认知的治疗方法。拟议的项目检查可能导致精神分裂症认知障碍的电路异常。

DESCRIPTION (provided by applicant): Schizophrenia is a debilitating disorder which affects 1% of the population at a substantial cost to the individual, their family and society. Cognitive ability is the best predictor of employment, social integration and relapse in schizophrenia, but current pharmacotherapies do not address cognitive dysfunction. A core component of cognition is working memory (WM), which depends upon proper activation of dorsolateral prefrontal cortex (DLPFC) circuitry, and both WM and DLPFC activation are impaired in schizophrenia. To identify therapeutic targets for improving WM, the underlying nature of DLPFC circuitry abnormalities must be identified. Parvalbumin (PV) basket cells synapse onto the perisomatic region of pyramidal cells and are critical for synchronizing neural populations to oscillate in the gamma range (30-90 Hz). Gamma oscillations are thought to underlie WM ability, and schizophrenia patient show impaired gamma oscillations during WM tasks. Recent evidence demonstrates that PV basket cell axonal arbors and synapses are significantly diminished if adequate levels of GAD67 are not available during development In schizophrenia DLPFC, GAD67 mRNA is undetectable in 45% of PV interneurons, suggesting these GAD67-negative, PV-positive interneurons form fewer connections with pyramidal cells. Thus, alterations in PV basket cell connections may contribute to the circuitry abnormalities underlying impaired WM in schizophrenia. To test the hypothesis that PV basket cell inputs are diminished in schizophrenia, pre- and postsynaptic markers are examined in DLPFC tissue from schizophrenia relative to comparison subjects. In Aim 1, a novel confocal microscopic method is used to test the hypothesis that DLPFC pyramidal somata receives fewer PV basket cell inputs in schizophrenia. PV basket cells synapsing onto pyramidal somata signal via GABAa receptors containing alpha subunits. Thus, in Aim 2, the same method is used to test the hypothesis that the number of alpha subunit clusters on pyramidal somal membranes is lower in schizophrenia. Recent evidence indicates that PV basket cell inputs onto pyramidal cells, but not interneurons, are important for gamma ocsillations. Thus, in Aim 3 the hypothesis that alpha subunits are exclusively lower in pyramidal cells is tested using dual-label in situ hybridization to determine the percentage of pyramidal cells and interneuons containing alpha mRNA in schizophrenia. Relevance: Schizophrenia affects over 3 million Americans at a cost of $62 billion a year, and cognitive ability is the best predictor of employment and relpase in these patients. No treatments which improve cognition in schizophrenia are currently available. The proposed project examines circuitry abnormalities which likely contribute to cognitive impairment in schizophrenia.