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，人们都知道癫痫中存在抑郁症的合并症，最近，抑郁症已被确定为癫痫的一个危险因素，突出了这些疾病在病理生理学上的重叠。然而，很少有研究涉及抑郁症和癫痫共发病的机制。压力是这两种疾病的触发因素，我们假设由下丘脑-垂体-肾上腺（HPA）轴介导的身体应激反应功能障碍可能在抑郁症和癫痫的合并症中发挥作用。抑郁症的一个显著特征是下丘脑轴的高度兴奋性，而癫痫活动激活下丘脑轴。HPA轴的输出是由室旁核（PVN）中的促肾上腺皮质激素释放激素（CRH）神经元介导的，其活性受到gaba能的强大控制。这一提议将验证下丘脑轴gaba能控制功能障碍导致下丘脑轴高兴奋性，从而导致癫痫易感性增加的假设。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，有条件的敲除调节HPA轴的主要GABAARs之一，Gabrd基因。我们打算将这些小鼠与CRH- cre小鼠杂交，以产生在调节HPA轴输出的CRH神经元中特异性存在gaba能缺陷的小鼠。此外，我们将研究初始发作损伤是否会改变PVN中GABAAR亚基的表达，就像它在其他脑区一样，从而导致下丘脑轴的高兴奋性和未来的癫痫发作。深入了解gaba能控制HPA轴在癫痫和抑郁症共发病中的作用，可能会为癫痫和抑郁症以及这两种疾病的共发病确定新的治疗靶点，这补充了NINDS通过研究减轻神经系统疾病负担的使命和确定神经系统疾病新潜在疗法的新战略计划。

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.