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）：γ-氨基丁酸（GABA）ERGIC抑制性局部电路神经元（LCN），其中包含钙结合蛋白（CBP）白蛋白（PV），其中包括篮子和枝形细胞，包括篮子和枝形素细胞，表现出快速的尖刺活性，并提供快速的perisish perison和axo neyvienty and artyviential nevaram-rassonvation pyram-pyram-pyram pyram-pyram invyrim pyram insvirnic cy pyram invyrim pyram。他们还从皮质皮质（CC）和丘脑皮质（TC）末端接收谷氨酸能输入。此外，它们通过间隙连接将它们电到电。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）的许多神经认知缺陷的基础，因此我们假设PV神经元的完整性可能在这种疾病中受到损害。 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分别在PV和CCK-免疫反应（IR）神经元上。此外，为了揭示是否可以选择性地改变PV轴突终端，我们将：（1）将GABA转运蛋白GAT-1和PV，CB或CCK的mRNA共定位，以及（2）（2）使用定量的实时反转录酶链量2）在激光捕获的锥体神经元中，优先富含由篮子和枝形吊灯细胞形成的突触。最后，我们将分别量化脑源性神经营养因子（BDNF）及其受体酪氨酸激酶TRKB的mRNA量，分别在激光捕获的锥体神经元和PV-或CB-IR细胞中，以测试缺乏的BDNF/TRKB信号对PVS的假设有助于PVIVE VIDIVE feative foricive foricive deficitive foricive deficitive foricive deficitive foricive forivics s ne。总之，这些实验可以从概念上提供有关SCZ神经认知缺陷如何通过重新校准PV神经元活性来纠正的新见解。