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: 8439885
• 负责人: KENNETH N FISH
• 金额: $ 29.83万
• 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/8439885
• 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. PUBLIC HEALTH RELEVANCE: Deficits in GABA neurotransmission associated with schizophrenia are believed to contribute to the impairments in certain cognitive functions that are core features of the illness. For the most part, current pharmacological treatments for schizophrenia are ineffective at improving cognitive function. These studies will provide much needed information about how GABAergic chandelier interneuron to pyramidal cell synapses, a potential pharmacological target, develop and are affected in schizophrenia.

描述(申请人提供)：精神分裂症是一种认知控制受损的神经发育障碍。这种损伤被认为至少部分是由于表达枝形吊灯细胞(CHC)的小白蛋白(PV)中皮质GABA神经传递的改变。CHC的轴突只针对锥体神经元的轴突起始段(AIS)，也就是动作电位产生的部位，因此CHC可以强烈地影响PYR细胞的输出和前额叶皮质(PFC)的活动。给定CHC的轴突发散，支配数百个相邻的PYR细胞，多个CHC的轴突可能会聚到一个PYR AIS上，形成一个独特的、垂直定向的终末阵列，称为盒。在精神分裂症患者的PFC中，GABA膜转运蛋白1(GAT1)免疫反应可检测到的墨盒密度降低了40%。这一发现可能反映了一种严重影响CHC亚群的疾病过程，因此这些CHC提供的轴突终末较少。因此，这些CHC瞄准的一些PYR AI没有接收足够数量的CHC终端来形成可识别的盒。支持这一解释的发现如下：1)在精神分裂症中，约50%的PFC PV神经元缺乏可检测到的GAD67 mRNA水平；2)在灵长类PFC中，CHC终末含有GAD67蛋白，但低至不含GAD65；以及3)在实验系统中，GAD67的耗尽会导致终末的丢失。因此，我们假设在CHC的子集中显著降低GAD67的表达导致支配某些PYR AIS的终末更少，从而使这些AIS中的一些不再与可识别的突触前CHC盒相关联。要了解精神分裂症患者CHC异常的发病机制，需要了解CHC到PYR AIS的输入在出生后发育过程中是如何精炼的。猴子PFC的初步数据显示，儿童时期向PYR AIS输入的CHC数量明显多于成年。这些发现表明，先前报道的正常猴PFC青春期GAT1免疫反应盒密度的降低是由于支配某些AIS的CHC终末数量的减少或修剪造成的。我们假设到PYR AIS的CHC末端输入在猴子PFC的青春期被修剪，并且这种减少解释了先前观察到的盒密度的发育变化。一项发现，即CHC末端丢失发生在猴子的青春期，这将支持这样的解释，即我们预测的精神分裂症每个AIS末端较少的结果反映了由于在CHC到AIS连接的修剪期间或之前，CHC末端中GAD67表达水平不足而导致的过度末端修剪。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中CHC终末的数量以及精神分裂症和非人类灵长类发育过程中CHC终末的相对平均GAD67蛋白水平。了解精神分裂症AIS的病理性质以及AIS神经支配减少的发展轨迹应该有助于洞察AIS的病理何时出现在发育中。 公共卫生相关性：与精神分裂症相关的GABA神经传递缺陷被认为是导致某些认知功能障碍的原因，而认知功能是这种疾病的核心特征。在很大程度上，目前精神分裂症的药物治疗在改善认知功能方面是无效的。这些研究将提供关于GABA能枝形吊灯中间神经元到锥体细胞突触的急需信息，这是一个潜在的药理靶点，在精神分裂症中如何发展和受到影响。