Mechanisms of Ligand-Induced GABA Receptor Plasticity

配体诱导 GABA 受体可塑性的机制

• 批准号: 7586713
• 负责人: RICHARD W OLSEN
• 金额: $ 23.24万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7586713
• 关键词: Allopregnanolone; Anesthetics; Animals; Antibodies; Benzodiazepines; Binding; Biochemical; Biological Assay; Biotinylation; Cell surface; Cells; Cerebellum; Chronic; Class; Computer information processing; Confocal Microscopy; Control Animal; Dendrites; Dependence; Development; Epilepsy; Ethanol; Exhibits; GABA Receptor; Goals; Hippocampal Formation; Hippocampus (Brain); Interneurons; Label; Ligands; Localized; Location; Measures; Mediating; Modeling; Molecular; Mus; Neuraxis; Neurons; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Physiological; Pilocarpine; Plastics; Positioning Attribute; Predisposition; Property; Prosencephalon; Recurrence; Research Personnel; Seizures; Site; Steroids; Structure of molecular layer of cerebellar cortex; Subgroup; Synapses; System; Temporal Lobe Epilepsy; Testing; Withdrawal; Work; analog; base; density; dentate gyrus; experience; gamma-Aminobutyric Acid; ganaxolone; granule cell; inhibitory neuron; interest; mouse model; nervous system disorder; neurochemistry; programs; receptor; response

The objectives of this component are to analyze the molecular mechanisms of chronic GABAergic ligand-induced plasticity in the central nervous system (CNS). Various plasticity-inducing treatments produce changes in levels of the GABAA receptor (GABAR) subunit alpha4 and its associated partners, gamma2 or 8, accompanied by altered sensitivity to endogenous neurosteroids. In this program, we have determined that alpha4beta3delta subunit-containing GABAR are extrasynaptically localized, involved in tonic inhibition, and the major target of modulation of CNS excitability by neurosteroids and anesthetics including ethanol, while being insensitive to benzodiazepines. In particular we showed by several lines of evidence that the alpha6beta3delta subtype of GABAR is very likely the target of action of ethanol in the cerebellum. This important discovery needs substantiation and forms the rationale for Aim I. We suggest that the alpha4/6beta3delta GABAR are both susceptible to plasticity and positioned to regulate excitability via neurosteroid-modulated tonic inhibition. In this project Aim II we will compare and contrast changes in GABAR following chronic steroid (extrasynaptic delta subunit-containing target) and chronic BZ (synaptic gamma2 subunit-containing target). In drug-treated mice, we will measure biochemically the levels of GABAR subunits in hippocampus and cerebellum and partnering of subunits using antibodies, as well as binding assays for GABAR levels and allosteric modulation indicative of subunit switches. In drug-treated primary cultured hippocampal neurons, we will measure the content of cell surface GABAR subunits and subunit partners using biotinylation. Plastic changes following chronic GABAergic drugs are relevant not only to the development of tolerance to clinically useful agents like benzodiazepines (BZ) as well as withdrawal and dependence, but also to the control of excitability by the GABA system. This in turn is critically important to normal CNS information processing and changes that occur in response to usual or unusual experiences (plasticity), including epileptogenic phenomena.

本部分的目的是分析慢性gaba能配体诱导中枢神经系统可塑性的分子机制。各种诱导可塑性的处理会产生GABAA受体（GABAR）亚基α 4及其相关伙伴γ 2或8水平的变化，并伴随着对