Leptin Modulates the Intrinsic Excitability of AgRP/NPY Neurons in the Arcuate Nucleus of the Hypothalamus
Leptin Modulates the Intrinsic Excitability of AgRP/NPY Neurons in the Arcuate Nucleus of the Hypothalamus
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DOI：
10.1523/jneurosci.4861-12.2014
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发表时间：
2014-04-16
影响因子：
5.3
通讯作者：
O'Connell, Kristen M. S.
中科院分区：
文献类型：
--
作者：
Baver, Scott B.;Hope, Kevin;O'Connell, Kristen M. S.
下丘脑弓状核（ARH）是调节食物摄入的关键脑区，也是瘦素在中枢神经系统中作用的主要区域。在瘦小鼠中，脂肪因子瘦素抑制神经肽Y（NPY）和刺豚鼠相关肽（AgRP）神经元活性，导致食物摄入减少。在这里，我们表明饮食诱导的小鼠肥胖与NPY神经元的持续激活以及瘦素未能降低放电率或使静息膜电位超极化有关。然而，饮食解除瘦素对神经元兴奋性影响的分子机制仍有待充分阐明。在瘦小鼠的NPY神经元中，Kv通道阻断剂4-氨基吡啶抑制瘦素诱导的输入阻力和峰电位率的变化。与此相一致，我们发现ARH NPY神经元有一个大的，瘦素敏感的延迟整流钾电流和瘦素敏感性，这种电流在饮食诱导的肥胖小鼠的神经元钝化。该电流主要由含Kv 2的通道携带，因为Kv 2通道抑制剂stromatoxin-1显著增加了瘦小鼠NPY神经元的自发放电率。在HEK细胞中，瘦素诱导Kv2.1的电压依赖性的显着的超极化转变，但没有密切相关的通道Kv2.2的功能的影响时，这些通道与瘦素受体LepRb的长亚型共表达。我们的研究结果表明，体细胞Kv2.1通道的动态调制调节神经肽Y神经元的内在兴奋性，调节自发活动和整合的突触输入到这些神经元在ARH。
The hypothalamic arcuate nucleus (ARH) is a brain region critical for regulation of food intake and a primary area for the action of leptin in the CNS. In lean mice, the adipokine leptin inhibits neuropeptide Y (NPY) and agouti-related peptide (AgRP) neuronal activity, resulting in decreased food intake. Here we show that diet-induced obesity in mice is associated with persistent activation of NPY neurons and a failure of leptin to reduce the firing rate or hyperpolarize the resting membrane potential. However, the molecular mechanism whereby diet uncouples leptin's effect on neuronal excitability remains to be fully elucidated. In NPY neurons from lean mice, the Kv channel blocker 4-aminopyridine inhibited leptin-induced changes in input resistance and spike rate. Consistent with this, we found that ARH NPY neurons have a large, leptin-sensitive delayed rectifier K+ current and that leptin sensitivity of this current is blunted in neurons from diet-induced obese mice. This current is primarily carried by Kv2-containing channels, as the Kv2 channel inhibitor stromatoxin-1 significantly increased the spontaneous firing rate in NPY neurons from lean mice. In HEK cells, leptin induced a significant hyperpolarizing shift in the voltage dependence of Kv2.1 but had no effect on the function of the closely related channel Kv2.2 when these channels were coexpressed with the long isoform of the leptin receptor LepRb. Our results suggest that dynamic modulation of somatic Kv2.1 channels regulates the intrinsic excitability of NPY neurons to modulate the spontaneous activity and the integration of synaptic input onto these neurons in the ARH.