Parvalbumin-Containing Neurons in Schizophrenia

精神分裂症中含有小白蛋白的神经元

• 批准号: 7146982
• 负责人: TSUNG-UNG W. WOO
• 金额: $ 32.6万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7146982
• 关键词: NMDA receptors; axon; behavioral /social science research tag; biological signal transduction; brain derived neurotrophic factor; calbindin; calcium binding protein; cerebral cortex; cholecystokinin; cognition disorders; gamma aminobutyrate; gene expression; glutamate transporter; human tissue; immunocytochemistry; laser capture microdissection; neurochemistry; neurons; polymerase chain reaction; postmortem; protein tyrosine kinase; pyramidal cells; schizophrenia; synapses; thalamocortical tract

DESCRIPTION (provided by applicant): The class of gamma-aminobutyric acid (GABA)ergic inhibitory local circuit neurons (LCNs) that contain the calcium binding protein (CBP) parvalbumin (PV), which include basket and chandelier cells, exhibit fast-spiking activities and furnish perisomatic and axo-axonic innervation of pyramidal neurons, respectively. They also receive glutamatergic inputs from corticocortical (CC) and thalamocortical (TC) terminals. In addition, they are electrically coupled via gap junctions. Via chemical and electrical synaptic connections, PV neurons regulate the oscillatory dynamics in the cerebral cortex. Because disruption of cortical oscillatory dynamics may underlie many of the neurocognitive deficits of schizophrenia (SCZ), we postulate that the integrity of PV neurons may be compromised in this disorder. To test the hypothesis that, in the prefrontal cortex, glutamatergic inputs to PV neurons via N-methyl-D-aspartate (NMDA) receptors may be selectively altered, in a cohort of 21 SCZ and 21 matched normal control subjects, we will: (1) Colocalize the mRNA for the NMDA NR2A subunit and the mRNA for PV, calbindin (CB), which is a CBP that is expressed by a class of LCNs that target the distal dendrites of PNs, or cholecystokinin (CCK), which identifies a class of regular-spiking basket cells that do not contain PV, and (2) Examine the appositions of CC and TC terminals, labeled by an antibody against the vesicular glutamate transporter vGluTI and 2, respectively, on PV- and CCK-immunoreactive (ir) neurons. Furthermore, in order to shed light on whether PV axonal terminals may be selectively altered, we will: (1) Colocalize the mRNA for the GABA transporter GAT-1 and the mRNA for PV, CB, or CCK, and (2) Utilize quantitative real-time reverse transcriptase polymerase chain reaction to quantitate the mRNA for GABAA receptor alpha 1 and 2 subunits, which are preferentially enriched in synapses formed by basket and chandelier cells, respectively, in laser-captured pyramidal neurons. Finally, we will quantitate the amount of mRNA for brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase TrkB in laser-captured pyramidal neurons and PV- or CB-ir cells, respectively, in order to test the hypothesis that deficient BDNF/TrkB signaling may contribute to the selective deficits of PV neurons. Together, these experiments may provide conceptually novel insight into how neurocognitive deficits of SCZ could potentially be corrected by re-calibration of PV neuronal activities.

描述（由申请人提供）：含有钙结合蛋白（CBP）小清蛋白（PV）的γ-氨基丁酸（GABA）能抑制性局部回路神经元（LCN），包括篮状细胞和枝状细胞，表现出快速尖峰活动，分别提供锥体神经元的体周和轴-轴神经支配。它们还接受来自皮质（CC）和丘脑皮质（TC）终末的丘脑能输入。此外，它们通过间隙结电耦合。通过化学和电突触连接，PV神经元调节大脑皮层中的振荡动力学。由于皮质振荡动力学的破坏可能是精神分裂症（SCZ）的神经认知缺陷的基础，我们假设PV神经元的完整性可能会受到损害。为了检验这一假设，即在前额叶皮层中，通过N-甲基-D-天冬氨酸（NMDA）受体向PV神经元的多巴胺能输入可能被选择性地改变，在21名SCZ和21名匹配的正常对照受试者的队列中，我们将：（1）共定位NMDA NR 2A亚基的mRNA和PV、钙结合蛋白（CB）的mRNA，其是由靶向PN的远端树突的一类LCN或胆囊收缩素（CCK）表达的CBP，所述胆囊收缩素（CCK）鉴定一类不含PV的规则尖峰篮状细胞，和（2）检查CC和TC末端的并置，分别在PV-和CCK-免疫反应（ir）神经元上用抗囊泡谷氨酸转运蛋白vGluTI和2的抗体标记。此外，为了阐明PV轴突终末是否可以选择性改变，我们将：（1）共定位GABA转运蛋白GAT-1的mRNA和PV、CB或CCK的mRNA，和（2）利用定量实时逆转录酶聚合酶链反应定量GABAA受体α 1和2亚基的mRNA，在激光捕获的锥体神经元中，其分别优先富集在由篮状细胞和枝形细胞形成的突触中。最后，我们将定量的mRNA的量为脑源性神经营养因子（BDNF）和其受体酪氨酸激酶TrkB在激光捕获的锥体神经元和PV或CB-IR细胞，分别，为了测试的假设，缺陷BDNF/TrkB信号可能有助于PV神经元的选择性缺陷。总之，这些实验可以提供概念上的新见解，SCZ的神经认知缺陷可能会被纠正PV神经元活动的重新校准。