Chandelier cell inputs to pyramidal neurons in schizophrenia and development

精神分裂症和发育过程中吊灯细胞对锥体神经元的输入

• 批准号: 8690618
• 负责人: KENNETH N FISH
• 金额: $ 30.11万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8690618
• 关键词: Action Potentials; Adolescence; Adult; Affect; Age; Antipsychotic Agents; Axon; Calcium-Binding Proteins; Cells; Cessation of life; Childhood; Confocal Microscopy; Data; Development; Disease; Figs - dietary; Fluorescence; Generations; Impairment; Interneurons; Knowledge; Label; Membrane Transport Proteins; Messenger RNA; Modeling; Monkeys; Morphology; Nature; Neurodevelopmental Disorder; Neurons; Output; Parvalbumins; Pathogenesis; Pathology; Pattern; Pharmaceutical Preparations; Pharmacological Treatment; Prefrontal Cortex; Presynaptic Terminals; Primates; Process; Proteins; Psychotic Mood Disorders; Pyramidal Cells; Relative (related person); Reporting; Schizophrenia; Signal Transduction; Site; Staging; Synapses; System; Testing; Time; base; cognitive control; cognitive function; density; early childhood; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; immunoreactivity; improved; insight; nerve supply; neurotransmission; nonhuman primate; postnatal; presynaptic; primate development; protein expression; research study

DESCRIPTION (provided by applicant): Schizophrenia is a neurodevelopmental disorder in which cognitive control is impaired. This impairment is thought to be due, at least in part, to altered cortical GABA neurotransmission in parvalbumin (PV) expressing chandelier cells (ChCs). The axons of ChCs exclusively target the axon initial segment (AIS) of pyramidal neurons (PYR), the site of action potential generation, and thus ChCs can powerfully influence PYR cell output and prefrontal cortex (PFC) activity. The axon of a given ChC diverges to innervate hundreds of neighboring PYR cells, and the axons of multiple ChCs may converge onto a single PYR AIS, forming a distinctive, vertically-oriented array of terminals termed a cartridge. In PFC of subjects with schizophrenia, the density of cartridges detectable by GABA membrane transporter-1 (GAT1) immunoreactivity is 40% lower. This finding could reflect a disease process that severely affects a subpopulation of ChCs such that these ChCs furnish fewer axon terminals. As a result, some PYR AIS targeted by these ChCs do not receive a sufficient number of ChC terminals to form a recognizable cartridge. This interpretation is supported by findings showing that 1) in schizophrenia, ~50% of PFC PV neurons lack detectable levels of GAD67 mRNA; 2) in primate PFC, ChC terminals contain GAD67 protein, but low to no GAD65; and 3) in experimental systems depletion of GAD67 results in loss of terminals. Thus, we hypothesize that markedly lower GAD67 expression in a subset of ChCs results in fewer terminals innervating some PYR AIS such that some of those AIS are no longer associated with a recognizable presynaptic ChC cartridge. Understanding the pathogenesis of ChC abnormalities in schizophrenia requires knowledge of how ChC to PYR AIS inputs are refined during postnatal development. Preliminary data in monkey PFC show that the number of ChC inputs to PYR AIS is significantly greater in childhood than in adulthood. These findings suggest that the previously reported reduction in GAT1- immunoreactive cartridge density that occurs during adolescence in normal monkey PFC results from a decrease, or pruning, of the number of ChC terminals that innervate certain AIS. We hypothesize that ChC terminal inputs to PYR AIS are pruned during adolescence in monkey PFC, and that this reduction explains the prior observations of developmental changes in cartridge density. A finding that ChC terminal loss occurs during adolescence in monkeys would support the interpretation that our predicted results of fewer terminals per AIS in schizophrenia reflects excessive terminal pruning due to insufficient levels of GAD67 expression in ChC terminals during or before pruning of ChC to AIS connections. To test our hypotheses we use multi-label fluorescence confocal microscopy to assess the number of ChC terminals per AIS and relative mean GAD67 protein levels in ChC terminals in schizophrenia and across non-human primate development. Knowing the nature of the pathology at the AIS in schizophrenia and the developmental trajectory of reduced AIS innervation should provide insight into when the pathology at the AIS arises developmentally.

描述（由申请人提供）：精神分裂症是一种神经发育障碍，其中认知控制受损。这种损害被认为是由于，至少部分地，在小清蛋白（PV）表达枝形细胞（ChCs）的皮质GABA神经传递改变。ChC的轴突专门靶向锥体神经元（PYR）的轴突起始段（AIS），即动作电位产生的部位，因此ChC可以有力地影响PYR细胞输出和前额叶皮层（PFC）活动。给定ChC的轴突分叉以神经支配数百个相邻的PYR细胞，并且多个ChC的轴突可以会聚到单个PYR AIS上，形成独特的垂直定向的末端阵列，称为盒。在精神分裂症受试者的PFC中，GABA膜转运蛋白-1（GAT 1）免疫反应性可检测到的药筒密度降低了40%。这一发现可能反映了严重影响ChC亚群的疾病过程，使得这些ChC提供更少的轴突终末。因此，这些ChC靶向的一些PYR AIS没有接收足够数量的ChC末端来形成可识别的盒。这一解释得到了以下发现的支持：1）在精神分裂症中，约50%的PFC PV神经元缺乏可检测水平的GAD 67 mRNA; 2）在灵长类PFC中，ChC末端含有GAD 67蛋白，但GAD 65含量低至无; 3）在实验系统中，GAD 67耗竭导致末端丢失。因此，我们假设，在一个子集的ChC的GAD 67的表达显着降低的结果在较少的终端支配一些PYR AIS，使这些AIS中的一些不再与可识别的突触前ChC盒。了解精神分裂症中ChC异常的发病机制需要了解ChC到PYR AIS的输入在产后发育期间如何细化。在猴PFC的初步数据表明，在童年比在成年时，输入到PYR AIS的ChC的数量显着更大。这些研究结果表明，以前报道的减少GAT 1免疫反应盒密度发生在青春期在正常猴PFC的结果减少，或修剪，神经支配某些AIS的ChC终端的数量。我们假设，ChC终端输入PYR AIS修剪在青春期的猴子PFC，这种减少解释了先前的观察盒密度的发展变化。发现ChC末端丢失发生在青春期的猴子将支持解释，我们的预测结果较少的终端每个AIS精神分裂症反映过度终端修剪由于GAD 67表达水平不足的ChC终端期间或之前修剪的ChC AIS连接。为了验证我们的假设，我们使用多标记荧光共聚焦显微镜来评估每个AIS的ChC末端的数量和精神分裂症和非人灵长类动物发育中ChC末端的相对平均GAD 67蛋白水平。了解精神分裂症AIS的病理性质和AIS神经支配减少的发展轨迹，应有助于了解AIS的病理何时在发育过程中出现。