Parvalbumin-Containing Neurons in Schizophrenia

精神分裂症中含有小白蛋白的神经元

• 批准号: 7477921
• 负责人: TSUNG-UNG W. WOO
• 金额: $ 24.62万
• 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 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7477921
• 关键词: Affect; Aminobutyric Acid; Aminobutyric Acids; Anterior; Antibodies; Brain-Derived Neurotrophic Factor; Brodmann' s area; Calcium-Binding Proteins; Calibration; Cells; Cerebral cortex; Chemicals; Cholecystokinin; Chromosome Pairing; Class; Coupled; Dendrites; Digoxigenin; Disease; Disruption; Distal; Exhibits; GABA Transporter 1; Gap Junctions; Glutamate Transporter; Glutamates; Immunohistochemistry; Label; Lasers; Light; Localized; Mediating; Messenger RNA; Myoepithelial cell; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurocognitive Deficit; Neurons; Parvalbumins; Pathology; Polymerase Chain Reaction; Population; Prefrontal Cortex; Presynaptic Terminals; Pyramidal Cells; Receptor Protein-Tyrosine Kinases; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Reverse Transcription; Role; Schizophrenia; Signal Transduction; Synapses; Testing; Time; calbindin; cohort; density; design; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; insight; laser capture microdissection; nerve supply; neurotransmission; novel; novel strategies; postsynaptic; presynaptic; programs; receptor; research study

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(申请人提供)：这类伽马氨基丁酸(GABA)能抑制局部环路神经元(LCN)含有钙结合蛋白(CBP)小白蛋白(PV)，包括篮状细胞和吊灯细胞，表现出快速放电活动，并分别为锥体神经元提供体周和轴突神经支配。它们也接受来自皮质(CC)和丘脑皮质(TC)终末的谷氨酸能输入。此外，它们还通过间隙结进行电耦合。通过化学和电突触连接，PV神经元调节大脑皮层的振荡动力学。由于皮层振荡动力学的破坏可能是精神分裂症(SCZ)许多神经认知缺陷的基础，我们推测在这种疾病中PV神经元的完整性可能受到损害。在21名SCZ和21名匹配的正常对照组受试者的队列中，为了验证这样的假设，即在前额叶皮质，通过N-甲基-D-天冬氨酸(NMDA)受体向PV神经元的谷氨酸能输入可能被选择性地改变，我们将：(1)将NMDA NR2A亚单位的mRNA与PV的mRNA、Calbindin(CB)、Calbindin(CB)、Calbindin(CB)，这是一种CBP，由一类靶向PNS远端树突的LCNs表达，或CCK(其识别一类不包含PV的规则尖峰细胞)，以及(2)检查CC和TC终末的位置分别用针对囊泡谷氨酸转运体vGluTI和2的抗体标记PV和CCK免疫反应(Ir)神经元。此外，为了阐明PV轴突终末是否可能被选择性地改变，我们将：(1)将GABA转运体GAT-1的mRNA与PV、CB或CCK的mRNA共定位，(2)利用实时定量逆转录聚合酶链式反应来定量GABAA受体α1和2亚单位的mRNA，这两个亚单位分别优先富含在激光捕获的锥体神经元中由篮状细胞和枝形吊灯细胞形成的突触中。最后，我们将对激光捕获的锥体神经元和PV或CB-ir细胞中脑源性神经营养因子(BDNF)及其受体酪氨酸激酶TrkB的mRNA进行定量，以验证BDNF/TrkB信号缺陷可能导致PV神经元选择性缺陷的假说。总之，这些实验可能为如何通过重新校准PV神经元活动来潜在地纠正SCZ的神经认知缺陷提供概念上的新见解。