Characterization of leptin's antidepressant activity

描述（由申请人提供）：抑郁症是一种使人衰弱和复发的精神疾病。大约一半的抑郁症患者对目前可用的抗抑郁药没有反应。该项目的长期目标是了解抑郁症的发病机制，并为这种疾病开发新的治疗方法。这是重新提交的竞争性更新我们目前的资金申请，以研究脂肪细胞衍生激素瘦素抗抑郁样作用的分子和细胞机制。我们已经提供了强有力的证据表明，瘦素具有抗抑郁症的特性，支持一个新的抑郁症的脂肪抑制假说。瘦素直接注入海马产生抗抑郁样作用，和消融的功能性瘦素受体，LepRb，在这个大脑区域诱导抑郁样行为，这表明在海马中的LepRb介导瘦素作用于抑郁行为的重要作用。我们已经取得了新的观察，主要在前脑海马能神经元（Lepr cKO）的LepRb消融导致抑郁样症状，并促进NMDA诱导的海马突触抑制。Lepr cKO小鼠中瘦素的抗抑郁样行为效应被消除。这些小鼠对选择性5-羟色胺再摄取抑制剂（SSRI）治疗有抗性，但对谷氨酸受体NMDA-NR 2B（也称为GluN 2B）拮抗剂有高度反应。这些发现导致了一个假设，即多巴胺能系统介导瘦素对抑郁行为的作用。我们建议确定1）海马谷氨酸神经传递在介导瘦素的抗抑郁样作用中的作用，以及2）海马树突棘（海马谷氨酸能突触的位点）的重塑对瘦素的抗抑郁样作用的贡献。这些研究将产生新的见解的分子和细胞机制瘦素作用于边缘系统，并导致抑郁症的新疗法的发展。 公共卫生相关性：重性抑郁症是一种严重的复发性精神疾病，在世界范围内非常普遍。目前可用的抗抑郁药物仅对一部分患者有效，治疗作用的开始需要数周至数月的治疗。该研究项目的目标是了解抑郁症相关行为的病理生理学和发病机制，并确定新的治疗分子和神经靶点。

DESCRIPTION (provided by applicant): Depression is a debilitating and recurring psychiatric disorder. Approximately half of the patients with depressive disorder fail to respond to currently available antidepressants. The long-term goal of this project is to understand the pathogenesis of depressive disorders and to develop new therapeutic approaches for this disease. This is a resubmission of the application for competitive renewal of our current funding to study the molecular and cellular mechanisms underlying the antidepressant-like effect of the adipocyte- derived hormone, leptin. We have provided strong evidence that leptin possesses antidepressant-like properties, supporting a new adipostatic hypothesis of depression. Direct infusion of leptin into the hippocampus produces antidepressant-like effects, and ablation of the functional leptin receptor, LepRb, in this brain region induces depressive-like behaviors, suggesting an essential role of LepRb in the hippocampus in mediating leptin action on depressive behaviors. We have made novel observations that ablation of LepRb principally in forebrain glutamatergic neurons (Lepr cKO) leads to depressive-like symptoms and facilitates NMDA-induced synaptic depression in the hippocampus. The antidepressant-like behavioral effects of leptin were abolished in Lepr cKO mice. These mice were resistant to selective serotonin reuptake inhibitor (SSRI) treatments but highly responsive to the glutamate receptor NMDA- NR2B (also termed GluN2B) antagonist. These findings led to the hypothesis that the glutamatergic system mediates leptin action on depressive behaviors. We propose to determine 1) the role of hippocampal glutamate neurotransmission in mediating the antidepressant-like effects of leptin, and 2) the contribution of remodeling of hippocampal dendritic spines, sites of glutamatergic synapses, to the antidepressant-like effects of leptin. These studies will generate novel insights into molecular and cellular mechanisms into leptin action in the limbic system and lead to the development of novel therapies for depression. PUBLIC HEALTH RELEVANCE: Major depression is a severe and recurrent mental illness that is highly prevalent worldwide. Currently available antidepressant drugs are only effective in a subset of patients, and the onset of therapeutic actions requires weeks to months of treatment. The goals of this research project are to understand the mechanisms of the pathophysiology and pathogenesis of depression-related behaviors and to identify novel molecular and neural targets for treatments.