Parvalbumin-Containing Neurons in Schizophrenia

描述（由申请人提供）：含有钙结合蛋白（CBP）小白蛋白（PV）的γ -氨基丁酸（GABA）能抑制性局部回路神经元（LCNs），包括篮状细胞和枝形细胞，表现出快速尖峰活动，分别提供锥体神经元的周围和轴-轴突神经支配。它们也接受来自皮质（CC）和丘脑皮质（TC）终端的谷氨酸能输入。此外，它们通过间隙连接电耦合。PV神经元通过化学和电突触连接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）的许多神经认知缺陷的基础，我们假设PV神经元的完整性可能在这种疾病中受到损害。为了验证在前额叶皮层，谷氨酸能通过n -甲基- d -天冬氨酸（NMDA）受体输入PV神经元可能被选择性改变的假设，在21名SCZ和21名匹配的正常对照受试者中，我们将：(1)的mRNA Colocalize NMDA NR2A亚单位和PV的信使rna, calbindin (CB),这是一个CBP所表达的一类LCNs目标pn的远端树突,或缩胆囊素(CCK),确定一个类的regular-spiking篮子细胞不含PV,和(2)检查CC和TC终端的同位语,标记的抗体对水泡谷氨酸转运体vGluTI和2,分别在PV - CCK-immunoreactive (ir)神经元。此外，为了阐明PV轴突末端是否可能被选择性改变，我们将：(1)共定位GABA转运体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定量GABAA受体α 1和α 2亚基的mRNA，这两个亚基分别在激光捕获的锥体神经元中由篮状细胞和枝形细胞形成的突触中优先富集。最后，我们将分别在激光捕获的锥体神经元和PV-或CB-ir细胞中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，以验证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，这些实验可能提供概念上新颖的见解，了解如何通过重新校准PV神经元活动来纠正SCZ的神经认知缺陷。

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.