Investigating GABAergic control of the HPA axis in the co-morbidity of depression

描述（由申请人提供）：几十年来，人们已经知道癫痫中存在抑郁症的共病，最近，抑郁症已被确定为癫痫的风险因素，突出了这些疾病的病理生理学的重叠。然而，很少有研究已经解决了介导的抑郁症和癫痫的共病的机制。压力是这两种疾病的触发器，我们假设，在身体的应激反应，介导的下丘脑-垂体-肾上腺（HPA）轴的功能障碍，并可能发挥作用的抑郁症和癫痫的共同发病率。抑郁症的一个标志性特征是HPA轴的过度兴奋，癫痫发作活动激活HPA轴。HPA轴的输出由室旁核（PVN）中的促肾上腺皮质激素释放激素（CRH）神经元介导，其活性受到GABA能的强有力控制。该提案将检验以下假设：HPA轴的GABA能控制功能障碍导致HPA轴过度兴奋，导致癫痫发作易感性增加。我们已经开发了一套复杂的工具来测试这一假设，包括一种新的，有条件的敲除一个主要的GABAARs调节HPA轴，Gabrd基因。我们打算将这些小鼠与CRH-Cre小鼠杂交，以产生具有GABA能缺陷的小鼠，所述GABA能缺陷特别是在调节HPA轴输出的CRH神经元中。此外，我们将调查是否初始癫痫发作损伤改变GABAAR亚单位在PVN的表达，因为它在其他脑区，从而导致HPA轴过度兴奋和未来的癫痫发作。深入了解GABA能控制HPA轴在癫痫和抑郁症共病中的作用，可能会为癫痫和抑郁症以及两者的共病确定新的治疗靶点，这补充了NINDS的使命，即通过研究和新的战略计划来减少神经系统疾病的负担，以确定神经系统疾病的新的潜在疗法。

DESCRIPTION (provided by applicant): It has been known for decades that there is a co-morbidity of depression in epilepsy and recently, depression has been identified as a risk factor for epilepsy, highlighting the overlap in the pathophysiology of these diseases. However, very few studies have addressed the mechanisms mediating the co-morbidity of depression and epilepsy. Stress is a trigger for both of these disorders, and we hypothesize that dysfunction in the body's stress response, mediated by the hypothalamic-pituitary-adrenal (HPA) axis, and may play a role in the co-morbidity of depression and epilepsy. A hallmark characteristic of depression is hyperexcitability of the HPA axis and seizure activity activates the HPA axis. The output of the HPA axis is mediated by corticotrophin-releasing hormone (CRH) neurons in the paraventricular nucleus (PVN), the activity of which are under robust GABAergic control. This proposal will test the hypothesis that dysfunction in GABAergic control of the HPA axis results in hyperexcitability of the HPA axis, leading to increased seizure susceptibility. We have developed a sophisticated set of tools to test this hypothesis, including a novel, conditional knockout of one of the principal GABAARs regulating the HPA axis, the Gabrd gene. We intend to cross these mice with CRH-Cre mice to generate mice with GABAergic deficits specifically in the CRH neurons regulating the output of the HPA axis. Further, we will investigate whether an initial seizure insult alters GABAAR subunit expression in the PVN, as it does in other brain regions, thereby leading to HPA axis hyperexcitability and future seizures. Insight into the role of GABAergic control of the HPA axis in the co-morbidity of epilepsy and depression may identify novel therapeutic targets for both epilepsy and depression as well as the co-morbidity of the two, which complements the mission of the NINDS to reduce the burden of neurological diseases through research and the new strategic plan to identify new potential therapies for neurological diseases.