GABAergic Control of Depression Related Brain States

GABA 能控制抑郁相关的大脑状态

基本信息

批准号：
8653990
负责人：
BERNHARD LUSCHER
金额：
$ 47.43万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-18 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8653990
关键词：
Address Affect Animal Model Antidepressive Agents Anxiety Autopsy Behavior Behavioral Biochemical Brain Brain-Derived Neurotrophic Factor Cell Adhesion Molecules Cell surface Cells Chronic Data Dissociation Dose Down-Regulation Drug Receptors Drug resistance Electroconvulsive Therapy Etiology Face GABA-A Receptor GABA-A receptor gamma2 subunit Genes Genetic Genetic Recombination Glutamate Decarboxylase Glutamate Receptor Glutamates Hippocampus (Brain)Interneurons Ketamine Lead Major Depressive Disorder Maps Mediating Mental Depression Modeling Molecular Mus N-Methyl-D-Aspartate Receptors N-Methylaspartate NMDA receptor antagonist Neurons Neurotrophic Tyrosine Kinase Receptor Type 2 Patients Phenotype Prefrontal Cortex Prosencephalon Pyramidal Cells Recurrence Research Slice Somatostatin Surface Symptoms Synapses Testing Time base cell type disability gamma-Aminobutyric Acid in vivo mouse model mutant nerve supply neuropeptide Y novel postsynaptic presynaptic public health relevance receptor research study response synaptic function transmission process

项目摘要

DESCRIPTION (provided by applicant): Major depressive disorder (MDD) is a leading cause of total disability with inadequate treatment options and unresolved etiology. However, increasing evidence suggests that genetic and environmental vulnerabilities may converge on deficits of GABAergic transmission as a possible, causative core symptom of MDD. Other lines of research point to changes in glutamatergic transmission as being associated with MDD. In particular, subanesthetic doses of the NMDAR antagonist ketamin have rapid and lasting antidepressant effects even in otherwise drug-resistant forms of MDD, pointing to altered function of NMDA receptors. We have established GABA-A receptor gamma2 subunit heterozygous mice as an animal model with excellent construct, face and predictive validity of partially drug resistant MDD. Preliminary data show that GABA-A receptor deficits in gamma2 subunit heterozygous cultures result in markedly reduced expression and function of glutamate receptors. Treatment of mutant cultures with ketamine results in reversal of these deficits. Conversely, mice with GABA-A receptor deficit delimited to forebrain interneurons show a robust antidepressant-like phenotype. We here address the overall hypothesis that MDD is caused by reduced synaptic input from select subtypes of cortical and hippocampal GABAergic interneurons to pyramidal cells. The ensuing GABAergic deficit and altered E/I imbalance, through adaptive mechanisms results in reduced expression and function of ionotropic glutamate receptors, along with reduced functional connectivity of neurons. Transient treatment with NMDA receptor antagonists such as ketamine reverses these deficits and, following dissociation of the drug from the receptor, restores normal glutamatergic transmission. To address this hypothesis we will analyze ketamine-induced changes in expression and function of glutamate receptors and behavior in cultured neurons, brain slices and mice, respectively. We will further test whether chronic treatment with currently used antidepressants has similar effects on glutamatergic transmission. Lastly, we will use genetic deletion of the gamma2 subunit gene in small subsets of interneurons to identify interneuron subclasses that control depression-related behavior. Collectively, our proposal will contribute a major conceptual advance in understanding of the substrate of major depression as well as AD action.