Characterization of leptin's antidepressant activity

描述(由申请者提供)：抑郁症是一种衰弱和反复出现的精神障碍。大约一半的抑郁症患者对目前可用的抗抑郁药物没有反应。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。这是我们目前研究脂肪细胞衍生激素瘦素抗抑郁药样作用的分子和细胞机制资金竞争续期申请的重新提交。我们提供了强有力的证据表明瘦素具有抗抑郁药样的特性，支持一种新的关于抑郁症的脂肪假说。将瘦素直接注入海马区可产生抗抑郁药样作用，而切除该脑区的功能性瘦素受体LepRb可诱导抑郁样行为，提示海马区LepRb在介导瘦素对抑郁行为的作用中起着重要作用。我们有新的观察到，消融LepRb主要在前脑谷氨酸能神经元(Lepr CKO)导致抑郁样症状，并促进NMDA诱导的海马区突触抑制。瘦素在Lepr CKO小鼠体内的抗抑郁药样行为作用被取消。这些小鼠对选择性5-羟色胺再摄取抑制剂(SSRI)治疗有抵抗力，但对谷氨酸受体NMDA-NR2B(也称为GluN2B)拮抗剂高度敏感。这些发现导致了一种假设，即谷氨酸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抗抑郁剂样作用中的作用，以及2)谷氨酸能突触部位--海马树突棘重塑在瘦素抗抑郁剂样作用中的作用。这些研究将对瘦素在边缘系统中作用的分子和细胞机制产生新的见解，并导致抑郁症新疗法的开发。

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.