Forebrain glutamatergic neurons mediate leptin action on depression-like behaviors and synaptic depression.
Forebrain glutamatergic neurons mediate leptin action on depression-like behaviors and synaptic depression.
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前脑谷氨酸能神经元介导瘦素对抑郁样行为和突触抑郁症的作用。
DOI：
10.1038/tp.2012.9
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发表时间：
2012
影响因子：
6.8
通讯作者：
Lu XY
中科院分区：
文献类型：
--
作者：
Guo M;Lu Y;Garza JC;Li Y;Chua SC;Zhang W;Lu B;Lu XY
谷氨酸系统与抑郁症的病理生理和抗抑郁药的作用机制有关。瘦素是一种脂肪细胞衍生的激素，具有抗抑郁的特性。然而，瘦素受体（Lepr）信号在谷氨酸能神经元中的功能作用仍有待阐明。在这项研究中，我们制造了条件敲除小鼠，选择性地切除位于前脑结构（包括海马和前额叶皮质）的谷氨酸能神经元中的长形Lepr。麻风cKO小鼠生长正常，体重正常。Lepr cKO小鼠的行为特征显示出抑郁症样的行为缺陷，包括快感缺乏、行为绝望、习得性无助和社交退缩增强，没有明显的焦虑迹象。此外，前脑谷氨酸能神经元Lepr的缺失促进了n -甲基-天冬氨酸（NMDA）诱导的海马长期突触抑制（LTD），而传统的LTD或长期增强（LTP）不受影响。促进的LTD诱导需要激活NMDA受体GluN2B （NR2B）亚基，因为它被选择性GluN2B拮抗剂完全阻断。此外，Lepr cKO小鼠对GluN2B拮抗剂的抗抑郁样行为作用高度敏感，但对瘦素有抗性。这些结果支持了谷氨酸能神经元中Lepr信号在调节抑郁相关行为和调节兴奋性突触强度中的重要作用，提示突触抑制与行为抑郁症的行为表现之间可能存在关联。
The glutamatergic system has been implicated in the pathophysiology of depression and the mechanism of action of antidepressants. Leptin, an adipocyte-derived hormone, has antidepressant-like properties. However, the functional role of leptin receptor (Lepr) signaling in glutamatergic neurons remains to be elucidated. In this study, we generated conditional knockout mice in which the long form of Lepr was ablated selectively in glutamatergic neurons located in the forebrain structures, including the hippocampus and prefrontal cortex (Lepr cKO). Lepr cKO mice exhibit normal growth and body weight. Behavioral characterization of Lepr cKO mice reveals depression-like behavioral deficits, including anhedonia, behavioral despair, enhanced learned helplessness and social withdrawal, with no evident signs of anxiety. In addition, loss of Lepr in forebrain glutamatergic neurons facilitates N-methyl--aspartate (NMDA)-induced hippocampal long-term synaptic depression (LTD), whereas conventional LTD or long-term potentiation (LTP) was not affected. The facilitated LTD induction requires activation of the NMDA receptor GluN2B (NR2B) subunit as it was completely blocked by a selective GluN2B antagonist. Moreover, Lepr cKO mice are highly sensitive to the antidepressant-like behavioral effects of the GluN2B antagonist but resistant to leptin. These results support important roles for Lepr signaling in glutamatergic neurons in regulating depression-related behaviors and modulating excitatory synaptic strength, suggesting a possible association between synaptic depression and behavioral manifestation of behavioral depression.
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影响因子：
64.8
作者：
Autry, Anita E.;Adachi, Megunai;Nosyreva, Elena;Na, Elisa S.;Los, Maarten F.;Cheng, Peng-fei;Kavalali, Ege T.;Monteggia, Lisa M.
通讯作者：
Monteggia, Lisa M.
影响因子：
3.5
作者：
DIAMOND, DM;BENNETT, MC;ROSE, GM
通讯作者：
ROSE, GM
影响因子：
3.5
作者：
Chen, Yue;Jiang, Ying;Mao, Yang
通讯作者：
Mao, Yang
影响因子：
10.6
作者：
Berman, RM;Cappiello, A;Krystal, JH
通讯作者：
Krystal, JH
影响因子：
64.5
作者：
Chen, H;Charlat, O;Morgenstern, JP
通讯作者：
Morgenstern, JP