Parvalbumin-Containing Neurons in Schizophrenia

精神分裂症中含有小白蛋白的神经元

• 批准号: 7243432
• 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 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7243432
• 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（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）类，包括篮状细胞和吊灯细胞，表现出快速放电活动，并分别提供锥体神经元的周神经支配和轴突神经支配。它们还接收来自皮质皮质 (CC) 和丘脑皮质 (TC) 终端的谷氨酸输入。此外，它们通过间隙连接进行电耦合。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根源，因此我们推测 PV 神经元的完整性可能在这种疾病中受到损害。为了检验这样的假设：在前额皮质中，通过 N-甲基-D-天冬氨酸 (NMDA) 受体对 PV 神经元的谷氨酸输入可能会被选择性改变，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) 将 NMDA NR2A 亚基的 mRNA 和 PV、钙结合蛋白的 mRNA 共定位 (CB)，它是由一类针对 PN 远端树突的 LCN 表达的 CBP，或胆囊收缩素 (CCK)，它识别一类不包含 PV 的常规尖峰篮细胞，以及 (2) 检查 CC 和 TC 末端的并置，由针对囊泡谷氨酸转运蛋白 vGluTI 的抗体标记， 2，分别针对PV-和CCK-免疫反应性(ir)神经元。此外，为了阐明 PV 轴突末端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，以及（2）利用定量实时逆转录酶聚合酶链反应来定量 GABAA 受体 α 1 和 2 亚基的 mRNA，它们是 在激光捕获的锥体神经元中，优先富集分别由篮子细胞和吊灯细胞形成的突触。最后，我们将分别定量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 量，以检验 BDNF/TrkB 信号传导缺陷可能导致 PV 神经元选择性缺陷的假设。总之，这些实验可能为 SCZ 的神经认知缺陷如何通过重新校准 PV 神经元活动来纠正提供概念上新颖的见解。