GABAergic Control of Depression Related Brain States

GABA 能控制抑郁相关的大脑状态

• 批准号: 9020824
• 负责人: BERNHARD LUSCHER
• 金额: $ 47.63万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 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/9020824
• 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; Electrophysiology (science); Etiology; Face; GABA-A Receptor; GABA-A receptor gamma2 subunit; Genes; Genetic; Genetic Recombination; Glutamate Decarboxylase; Glutamate Receptor; Glutamates; Health; Hippocampus (Brain); Interneurons; Ketamine; Lead; Major Depressive Disorder; Maps; Mediating; Mental Depression; Microarray Analysis; 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; antidepressant effect; base; cell type; disability; gamma-Aminobutyric Acid; in vivo; mouse model; mutant; nerve supply; neuropeptide Y; novel; postsynaptic; presynaptic; receptor; research study; response; synaptic function; transmission process

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.

描述（由申请人提供）：重度抑郁症（MDD）是总残疾的主要原因，治疗方案不足和无法解决的病因。但是，越来越多的证据表明，遗传和环境脆弱性可能会融合GABA能传播的缺陷，这是MDD的一种可能的核心症状。其他研究线表明，谷氨酸能传播的变化与MDD相关。特别是，即使在其他耐药的MDD形式中，NMDAR拮抗剂酮蛋白的亚警觉剂量也具有快速而持久的抗抑郁作用，这表明NMDA受体的功能改变了。我们已经建立了GABA-A受体Gamma2亚基杂合小鼠作为一种动物模型，具有出色的构造，面部和预测性的耐药性MDD。初步数据表明，γ2亚基杂合培养物中的GABA-A受体缺陷导致谷氨酸受体的表达和功能明显降低。用氯胺酮处理突变培养物会导致这些缺陷的逆转。相反，用GABA-A受体缺陷到前脑间神经元的小鼠表现出强大的抗抑郁样表型。我们在这里解决了总体假设，即MDD是由从皮质和海马GABA能中间神经元到金字塔细胞的某些亚型的突触输入降低引起的。随之而来的GABA能赤字和通过自适应机制改变了E/I失衡，导致离子型谷氨酸受体的表达和功能降低，以及神经元的功能连通性降低。 NMDA受体拮抗剂（例如氯胺酮）的瞬时治疗会逆转这些缺陷，并在从受体中解散药物后，恢复了正常的谷氨酸能传播。为了解决这一假设，我们将分别分析氯胺酮诱导的谷氨酸受体的表达和功能变化以及培养的神经元，脑切片和小鼠的行为。我们将进一步测试当前使用的抗抑郁药的慢性治疗是否对谷氨酸能传播具有相似的影响。最后，我们将使用小型中间神经元子集中γ2亚基基因的遗传缺失来识别控制与抑郁相关行为的中间元亚类。总的来说，我们的建议将在理解严重抑郁症和广告行动的基础方面做出重大概念上的进步。