Cell-type specific GABA signaling is required for newborn neuron incorporation

新生神经元整合需要细胞类型特异性 GABA 信号传导

• 批准号: 8696836
• 负责人: ANDRE H LAGRANGE
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8696836
• 关键词: Acute; Adult; Affect; Animal Model; Brain; Brain Injuries; Cell Death; Cells; Chronic; Cognitive deficits; Development; Devices; Drug Delivery Systems; Electrodes; Embryo; Epilepsy; Evolution; GABA Receptor; Goals; Growth; Image; Immunofluorescence Immunologic; Individual; Injury; Interneurons; Kinetics; Knockout Mice; Ligands; Location; Measures; Mediating; Mediator of activation protein; Membrane Potentials; Membrane Proteins; Molecular Profiling; Mus; Neurologic; Neurons; Neurotransmitters; Outcome; Pattern; Pharmaceutical Preparations; Pharmacological Treatment; Process; Property; Protein Isoforms; Protein Subunits; Proteins; Refractory; Residual state; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Transduction; Slice; Staging; Symptoms; Synapses; Synaptic Cleft; System; Techniques; Testing; Time; Transcript; Translating; Transplantation; Traumatic Brain Injury; Veterans; adult neurogenesis; age related; axonal sprouting; base; biocytin; biophysical properties; cell type; cohort; gamma-Aminobutyric Acid; insight; mRNA Expression; meetings; migration; morphogens; nerve stem cell; nervous system disorder; neurogenesis; newborn neuron; novel; prevent; programs; protein complex; protein expression; receptor; receptor expression; receptor function; response; synaptic inhibition; voltage clamp

DESCRIPTION (provided by applicant): Traumatic brain injury is arguably the most significant neurological problem affecting our Veterans, leading to such devastating problems as refractory epilepsy and debilitating cognitive deficits. While the initial injury is important in determining eventual outcome, many of these problems do not manifest themselves until several years later. These delayed sequelae are thought to be due to pathological plasticity, including cell death, axonal sprouting, and changes in protein expression. Recently, the study of adult neurogenesis has emerged as a promising approach to provide both insight into the mechanisms of and potential treatment for brain injury. Transplanted embryonic interneurons have been used to ameliorate symptoms in a number of animal models of neurological disorders, and endogenous neurogenesis is robustly enhanced following brain injury. However, many of these newborn neurons are morphologically and functionally very abnormal, and may actually contribute to pathological changes following brain injury. A key hole in our understanding of pathological postinjury plasticity is an understanding o the signals directing how newborn neurons become incorporated into normal adult circuits. GABAA Receptors (GABARs) are particularly crucial morphogenic molecules directing neuronal proliferation, migration and synaptic integration. GABARs are heteropentameric protein complexes, typically containing 2 1, 2 2 and either a single 3 or 4 subunit protein. The identity o the 1 subunit isoform (11-6) is a key determinant of GABAR function, capable of producing profound differences in the kinetic properties and pharmacological sensitivity of GABARs. While 11 containing GABARs are the primary mediators of synaptic inhibition in mature neurons, there is a progression from 14 to 12,3 to 11 predominant GABAergic signaling that is an extraordinarily consistent finding in both embryonic neurons, as well as newborn neurons of the adult. A similar program of expression has also frequently encountered following already established neurons following adult brain injury. While GABA generally evokes inhibitory responses, activation of GABARs during this transitional period produces depolarizing responses, allowing GABA to serve as a powerful morphogen. Perturbations of depolarizing GABA cause aberrant neuronal maturation that depends critically on the cell type (interneuron vs principal cell) and developmental stage in question. While it is clear that GABAR function depends critically on the subunit combination, the significance of specific GABAR expression patterns during neuronal incorporation remain very poorly understood. In order to elucidate the role of specific GABAR subunit combinations, we will characterize the time-dependent evolution of GABAR subunit isoform expression, as well as the biophysical properties of the predominant GABARs being expressed. Finally acute brain slice recording with post-hoc morphological and immunocytochemical analysis will be used to correlate the changes in GABAergic signaling as a function of cell-type and maturational state. The overarching hypothesis is that the expression of specific GABAR subunit isoforms with unique biophysical properties are spatially and temporally locked with neuronal maturation in a cell-type specific manner to effectively mediate the evolving roles of GABAergic signaling required for incorporation into functional circuits. Our long term goal is to understand how this system becomes pathologically recapitulated following brain injury, and use this information to develop specific pharmacological treatments to prevent and treat the chronic neurological sequelae of brain injury.

描述（由申请人提供）： 创伤性脑损伤可以说是影响退伍军人的最重要的神经系统问题，导致难治性癫痫和认知缺陷等毁灭性问题。虽然最初的伤害对于决定最终的结果很重要，但其中许多问题直到几年后才会显现出来。这些延迟的后遗症被认为是由于病理可塑性造成的，包括细胞死亡、轴突出芽和蛋白质表达的变化。最近，成人神经发生的研究已成为一种有前途的方法，可以深入了解脑损伤的机制和潜在的治疗方法。移植的胚胎中间神经元已被用于改善许多神经系统疾病动物模型的症状，并且脑损伤后内源性神经发生显着增强。然而，许多新生神经元在形态和功能上都非常异常，实际上可能导致脑损伤后的病理变化。我们理解病理性损伤后可塑性的一个关键漏洞是理解指导新生神经元如何融入正常成人回路的信号。 GABAA 受体 (GABAR) 是指导神经元增殖、迁移和突触整合的特别重要的形态发生分子。 GABAR 是异五聚体蛋白质复合物，通常包含 2 1、2 2 和单个 3 或 4 亚基蛋白质。 1 亚基异构体 (11-6) 的特性是 GABAR 功能的关键决定因素，能够在 GABAR 的动力学特性和药理学敏感性上产生深刻的差异。虽然含有 GABAR 的 11 是成熟神经元中突触抑制的主要介质，但主要的 GABA 信号从 14 到 12,3 到 11 的进展，这在胚胎神经元以及成人的新生神经元中都是非常一致的发现。成人脑损伤后已经建立的神经元也经常遇到类似的表达程序。虽然 GABA 通常会引起抑制反应，但在此过渡期间 GABAR 的激活会产生去极化反应，使 GABA 能够充当强大的形态发生素。去极化 GABA 的扰动会导致异常的神经元成熟，这在很大程度上取决于细胞类型（中间神经元与主细胞）和相关的发育阶段。虽然很明显 GABAR 功能关键取决于亚基组合，但神经元掺入过程中特定 GABAR 表达模式的重要性仍然知之甚少。为了阐明特定 GABAR 亚基组合的作用，我们将描述 GABAR 亚基异构体表达的时间依赖性进化，以及所表达的主要 GABAR 的生物物理特性。最后，急性脑切片记录与事后形态学和免疫细胞化学分析将用于将 GABA 信号的变化与细胞类型和成熟状态的函数相关联。总体假设是，具有独特生物物理特性的特定 GABAR 亚基异构体的表达在空间和时间上以细胞类型特异性方式与神经元成熟锁定，以有效介导纳入功能回路所需的 GABA 信号的进化作用。我们的长 长期目标是了解脑损伤后该系统如何在病理上重现，并利用这些信息开发特定的药物治疗方法，以预防和治疗脑损伤的慢性神经系统后遗症。