权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

批准号：
8802848
负责人：
ANDRE H LAGRANGE
金额：
--
依托单位：
VETERANS HEALTH ADMINISTRATION
依托单位国家：
美国
项目类别：
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/8802848
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

项目摘要

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）：