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

描述(申请人提供)：几十年来，人们已经知道在癫痫中存在抑郁的共同发病率，最近，抑郁被确定为癫痫的一个危险因素，突显了这些疾病的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同发病的机制。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共同发病中发挥作用。抑郁症的一个特征是HPA轴的过度兴奋，而癫痫发作激活了HPA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，其活动受到强大的GABA能控制。这一建议将检验这样一种假设，即GABAA能控制HPA轴的功能障碍会导致HPA轴的过度兴奋，从而导致癫痫易感性的增加。我们已经开发了一套复杂的工具来检验这一假说，包括一种新颖的、有条件的敲除调节HPA轴的主要GABA受体之一的Gabrd基因。我们打算将这些小鼠与CRH-CRE小鼠杂交，以产生GABA能缺陷的小鼠，特别是调节HPA轴输出的CRH神经元。此外，我们将调查最初的癫痫发作是否会改变PVN中GABAAR亚单位的表达，就像它在其他脑区所做的那样，从而导致HPA轴过度兴奋和未来的癫痫发作。深入了解GABA对HPA轴的控制在癫痫和抑郁症共同发病中的作用可能会确定癫痫和抑郁症的新治疗靶点以及两者的共同发病率，这补充了NINDS的使命，即通过研究和新的战略计划来寻找神经疾病的新潜在疗法来减轻神经疾病的负担。 公共卫生相关性：洞察癫痫和抑郁症显著共同发病的潜在机制，将对这两种疾病以及两者共同发病具有治疗潜力。机体的应激反应受主要抑制性神经递质GABA的控制，分别参与了这两种疾病的病理生理过程，我们推测可能参与了这两种疾病的共同发病。我们开发了一种独特的小鼠模型，该模型缺乏对应激反应的GABA能调节，以研究其对抑郁症和癫痫共同发病的影响。

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. PUBLIC HEALTH RELEVANCE: Insight into mechanisms underlying the significant co-morbidity of epilepsy and depression will have therapeutic potential for both of these disorders as well as the co-morbidity of the two. The body's stress response, which is under the control of the major inhibitory neurotransmitter, GABA, has been implicated in the pathophysiology of these two diseases separately and we hypothesize may be involved in the co-morbidity. We have developed a unique mouse model, which is deficient in the GABAergic regulation of the stress response, to investigate the impact on the co-morbidity of depression and epilepsy.