Deficits in cortical basket cell signaling in schizophrenia

精神分裂症皮质篮细胞信号传导缺陷

基本信息

批准号：
8050160
负责人：
JILL RENEE' Glausier
金额：
$ 4.84万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-12-01 至 2011-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8050160
关键词：
Address Affect American Autopsy Axon Calcium-Binding Proteins Clinical Cognition Cognitive Confocal Microscopy Data Delusions Development Disease Drug Delivery Systems Employment Enzymes Family Frequencies GABA Receptor Glutamate Decarboxylase Goals Hallucinations Human Image Analysis Impaired cognition Impairment In Situ Hybridization Individual Interneurons Knowledge Label Learning Mediating Membrane Messenger RNA Methods Microscopic Monkeys Myoepithelial cell Nature Neurons Parvalbumins Patients Perception Performance Pharmacotherapy Population Prefrontal Cortex Presynaptic Terminals Process Protein Subunits Proteins Pyramidal Cells Relapse Relative (related person)Research Schizophrenia Schools Short-Term Memory Signal Transduction Social Functioning Societies Synapses Testing Tissues base cost density gamma-Aminobutyric Acid hippocampal pyramidal neuron improved mRNA Expression neural circuit neuronal cell body novel postsynaptic presynaptic receptor relating to nervous system research study social cognition social integration therapeutic target tool

项目摘要

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.

描述（由申请人提供）：精神分裂症是一种使人衰弱的疾病，对人口，其家庭和社会的巨额成本影响1％的人口。认知能力是精神分裂症中就业，社会融合和复发的最佳预测指标，但是当前的药物疗法无法解决认知功能障碍。认知的核心组成部分是工作记忆（WM），取决于背外侧前额叶皮层（DLPFC）电路的适当激活，而在精神分裂症中，WM和DLPFC激活都受损。为了确定改善WM的治疗靶标，必须确定DLPFC电路异常的潜在性质。白蛋白（PV）篮细胞突触到锥体细胞的围核区域，对于同步神经种群至关重要，以振荡在伽马范围内（30-90 Hz）。人们认为伽马振荡是WM能力的基础，精神分裂症患者在WM任务期间表现出γ振荡受损。最近的证据表明，如果在精神分裂症DLPFC的开发过程中无法获得足够水平的GAD67，则PV篮细胞轴突轴承和突触会显着减少，GAD67 mRNA在45％的PV Interneurons中无法检测到GAD67-NECH67-NECH67-NECHATIAL，PV型，PV-POSSIDINE NENERONS与PV-PV-PosIteNERONS connections connections connections connections connections connections connections。因此，PV篮细胞连接的改变可能会导致精神分裂症中WM损害的电路异常。为了测试精神分裂症中PV篮细胞输入减少的假设，相对于比较受试者，在精神分裂症的DLPFC组织中检查了前后突触后标记。在AIM 1中，一种新型的共聚焦显微镜方法用于检验以下假设：DLPFC锥体somata在精神分裂症中获得的PV篮细胞输入较少。 PV篮细胞通过包含α亚基的GABAA受体突触到锥体somata信号。因此，在AIM 2中，使用相同的方法来检验以下假设：在精神分裂症中，锥体som膜上α亚基簇的数量较低。最近的证据表明，PV篮细胞在锥体细胞上输入（而不是中间神经元）对于γ刻度很重要。因此，在AIM 3中，使用双标记的原位杂交测试了锥体细胞中α亚基仅较低的假设，以确定精神分裂症中含有αmRNA的锥体细胞和含有alpha mRNA的中间的百分比。相关性：精神分裂症每年影响超过300万美国人，成本为620亿美元，而认知能力是这些患者就业和利用酶的最佳预测指标。目前尚无改善精神分裂症认知的治疗方法。拟议的项目研究了电路异常，这可能导致精神分裂症的认知障碍。