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，治疗方案不足，病因不明。然而，越来越多的证据表明，遗传和环境脆弱性可能集中在gaba能传递缺陷上，这可能是重度抑郁症的一个致病核心症状。其他研究指出，谷氨酸传递的变化与重度抑郁症有关。特别是，亚麻醉剂量的NMDA拮抗剂氯胺酮即使在其他耐药形式的MDD中也具有快速和持久的抗抑郁作用，这表明NMDA受体的功能发生了改变。我们建立了GABA-A受体γ - 2亚基杂合小鼠作为部分耐药MDD的动物模型，具有良好的构建性、可面对性和预测有效性。初步数据显示，γ ma2亚基杂合培养中GABA-A受体缺失导致谷氨酸受体的表达和功能显著降低。用氯胺酮治疗突变体培养可逆转这些缺陷。相反，GABA-A受体缺陷局限于前脑中间神经元的小鼠表现出强大的抗抑郁样表型。我们在这里提出了一个总体假设，即MDD是由皮层和海马gaba能中间神经元的特定亚型向锥体细胞的突触输入减少引起的。随之而来的gaba能缺陷和改变的E/I失衡，通过适应性机制导致嗜离子性谷氨酸受体的表达和功能减少，以及神经元功能连通性降低。用NMDA受体拮抗剂（如氯胺酮）短暂治疗可逆转这些缺陷，并在药物与受体分离后，恢复正常的谷氨酸能传递。为了验证这一假说，我们将分别分析氯胺酮在培养神经元、脑切片和小鼠中引起的谷氨酸受体表达和功能以及行为的变化。我们将进一步测试目前使用的抗抑郁药物的慢性治疗是否对谷氨酸传递有类似的影响。最后，我们将利用中间神经元小亚群中gamma2亚基基因的遗传缺失来鉴定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理解重度抑郁症的基础以及AD的作用。

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.