Leptin induces a novel form of NMDA receptor-dependent long-term depression.
Leptin induces a novel form of NMDA receptor-dependent long-term depression.
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DOI：
10.1111/j.1471-4159.2005.03375.x
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发表时间：
2005-10
影响因子：
4.7
通讯作者：
Harvey J
中科院分区：
文献类型：
--
作者：
Durakoglugil M;Irving AJ;Harvey J
越来越明显的是，瘦素激素在调节海马功能中起着重要作用。事实上，瘦素可以增强NMDA受体的激活并促进海马长期增强（LTP）。此外，瘦素受体功能失调的肥胖啮齿动物海马突触可塑性受损。本研究表明，在兴奋性增强的条件下（在不含Mg2+的培养基中或GABAA受体被阻断后），瘦素在海马CA1区诱导了一种新型的长期抑郁（LTD）。在D-AP5存在的情况下，leptin诱导的LTD明显减弱，表明它依赖于NMDA受体的突触激活。此外，低频刺激诱发的LTD阻断了瘦素的作用。相比之下，mGluRs对瘦素诱导的LTD没有贡献，因为mGluR拮抗剂既不能阻止也不能逆转这一过程。瘦素诱导LTD的信号机制独立于ras - raf - mapk信号通路，但在抑制PI 3-激酶或蛋白磷酸酶1和2A后显著增强。这些数据表明，在兴奋性增强的条件下，瘦素诱导了一种新形式的同突触LTD，这进一步强调了该激素在调节NMDA受体依赖性海马突触可塑性中的关键作用。
It is becoming apparent that the hormone leptin plays an important role in modulating hippocampal function. Indeed, leptin enhances NMDA receptor activation and promotes hippocampal long-term potentiation (LTP). Furthermore obese rodents with dysfunctional leptin receptors display impairments in hippocampal synaptic plasticity. Here we demonstrate that under conditions of enhanced excitability (evoked in Mg2+-free medium or following blockade of GABAA receptors), leptin induces a novel form of long-term depression (LTD) in area CA1 of the hippocampus. Leptin-induced LTD was markedly attenuated in the presence of D-AP5, suggesting that it is dependent on the synaptic activation of NMDA receptors. In addition, low frequency stimulus-evoked LTD occluded the effects of leptin. In contrast, mGluRs did not contribute to leptin-induced LTD as mGluR antagonists failed to either prevent or reverse this process. The signaling mechanisms underlying leptin-induced LTD were independent of the Ras-Raf-MAPK-signaling pathway, but were markedly enhanced following inhibition of either PI 3-kinase or protein phosphatases 1 and 2A. These data indicate that under conditions of enhanced excitability, leptin induces a novel form of homosynaptic LTD, which further underscores the proposed key role for this hormone in modulating NMDA receptor-dependent hippocampal synaptic plasticity.
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