Department of Biochemistry, University of Washington School of Medicine, Seattle, WA 98195, USA.
Proc Natl Acad Sci U S A. 2013 Sep 3;110(36):14765-70. doi: 10.1073/pnas.1314137110. Epub 2013 Aug 20.
Diphtheria toxin-mediated, acute ablation of hypothalamic neurons expressing agouti-related protein (AgRP) in adult mice leads to anorexia and starvation within 7 d that is caused by hyperactivity of neurons within the parabrachial nucleus (PBN). Because NMDA glutamate receptors are involved in various synaptic plasticity-based behavioral modifications, we hypothesized that modulation of the NR2A and NR2B subunits of the NMDA receptor in PBN neurons could contribute to the anorexia phenotype. We observed by Western blot analyses that ablation of AgRP neurons results in enhanced expression of NR2B along with a modest suppression of NR2A. Interestingly, systemic administration of LiCl in a critical time window before AgRP neuron ablation abolished the anorectic response. LiCl treatment suppressed NR2B levels in the PBN and ameliorated the local Fos induction that is associated with anorexia. This protective role of LiCl on feeding was blunted in vagotomized mice. Chronic infusion of RO25-6981, a selective NR2B inhibitor, into the PBN recapitulated the role of LiCl in maintaining feeding after AgRP neuron ablation. We suggest that the accumulation of NR2B subunits in the PBN contributes to aphagia in response to AgRP neuron ablation and may be involved in other forms of anorexia.
在成年小鼠中，白喉毒素介导的、表达 AgRP（刺鼠相关蛋白）的下丘脑神经元的急性消融会导致厌食和饥饿，这是由于臂旁核（PBN）内神经元的过度活跃引起的。因为 NMDA 谷氨酸受体参与各种基于突触可塑性的行为改变，我们假设 PBN 神经元中 NMDA 受体的 NR2A 和 NR2B 亚基的调制可能有助于厌食表型。我们通过 Western blot 分析观察到，AgRP 神经元消融导致 NR2B 的表达增强，同时 NR2A 略有抑制。有趣的是，在 AgRP 神经元消融前的关键时间窗口内系统给予 LiCl 可消除厌食反应。LiCl 处理抑制了 PBN 中的 NR2B 水平，并改善了与厌食相关的局部 Fos 诱导。在迷走神经切断的小鼠中，LiCl 对进食的这种保护作用减弱。慢性输注选择性 NR2B 抑制剂 RO25-6981 到 PBN 中重现了 LiCl 在 AgRP 神经元消融后维持进食的作用。我们认为，PBN 中 NR2B 亚基的积累导致对 AgRP 神经元消融的厌食反应，并且可能涉及其他形式的厌食。
