GABAergic Control of Depression Related Brain States

描述（由申请人提供）：重度抑郁症（MDD）是导致完全残疾的主要原因，治疗选择不足，病因不明。然而，越来越多的证据表明，遗传和环境的脆弱性可能会汇聚在缺陷的GABA能传输作为一个可能的，致病的MDD的核心症状。其他研究路线指出谷氨酸能传输的变化与MDD相关。特别是，亚麻醉剂量的NMDAR拮抗剂氯胺酮具有快速和持久的抗抑郁作用，即使在其他耐药形式的MDD中，这表明NMDA受体的功能改变。我们建立了GABA-A受体γ 2亚基杂合子小鼠作为部分耐药MDD的动物模型，该模型具有良好的结构、外观和预测有效性。初步数据显示，γ 2亚基杂合培养物中GABA-A受体缺陷导致谷氨酸受体的表达和功能显著降低。用氯胺酮处理突变培养物可逆转这些缺陷。相反，GABA-A受体缺陷限定于前脑中间神经元的小鼠显示出强大的抗抑郁药样表型。我们在这里解决的总体假设，抑郁症是由减少突触输入从皮质和海马GABA能中间神经元的选择亚型锥体细胞。随后的GABA能缺陷和改变的E/I失衡，通过适应性机制导致离子型谷氨酸受体的表达和功能降低，沿着神经元功能连接性降低。用NMDA受体拮抗剂（如氯胺酮）进行短暂治疗可逆转这些缺陷，并在药物与受体解离后恢复正常的多巴胺能传递。为了解决这一假设，我们将分析氯胺酮诱导的谷氨酸受体的表达和功能的变化和培养的神经元，脑切片和小鼠的行为，分别。我们将进一步测试目前使用的抗抑郁药的慢性治疗是否对多巴胺能传递有类似的作用。最后，我们将使用一小部分中间神经元中gamma 2亚基基因的遗传缺失来识别控制抑郁相关行为的中间神经元亚类。总的来说，我们的建议将有助于一个重大的概念进步，在理解的基板的严重抑郁症以及AD的行动。

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.