GABAergic Control of Depression Related Brain States

描述(由申请人提供)：严重抑郁障碍(MDD)是导致完全残疾的主要原因，治疗方案不充分，病因尚未解决。然而，越来越多的证据表明，遗传和环境脆弱性可能汇聚在GABA能传递缺陷上，作为MDD的一种可能的致病核心症状。其他研究指出，谷氨酸能传递的变化与MDD有关。特别是，麻醉下剂量的NMDAR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受体的功能发生了变化。我们建立了GABA-A受体Gamma2亚基杂合子小鼠作为部分耐药MDD的良好结构、外观和预测有效性的动物模型。初步数据显示，在伽马2亚基杂合培养中，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，前脑中间神经元GABA-A受体缺陷的小鼠表现出强健的抗抑郁药样表型。我们在这里提出了MDD的总体假设，即MDD是由选定的皮质和海马GABA能中间神经元到锥体细胞的突触输入减少引起的。随之而来的GABA能缺陷和E/I失衡，通过适应性机制导致离子型谷氨酸受体表达和功能的减少，以及神经元功能连接的减少。用NMDA受体拮抗剂如氯胺酮进行短暂治疗可以逆转这些缺陷，并在药物与受体解离后恢复正常的谷氨酸能传递。为了解决这一假设，我们将分析氯胺酮诱导的谷氨酸受体表达和功能的变化，以及培养神经元、脑片和小鼠的行为。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能传递有类似的效果。最后，我们将使用基因缺失的中间神经元小亚群中的Gamma2亚单位基因来识别控制抑郁相关行为的中间神经元亚类。总而言之，我们的建议将有助于在理解严重抑郁症的基础以及AD的作用方面取得重大的概念性进展。

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.