Preferential enhancement of GluN2B-containing native NMDA receptors by the endogenous modulator 24S-hydroxycholesterol in hippocampal neurons.
Preferential enhancement of GluN2B-containing native NMDA receptors by the endogenous modulator 24S-hydroxycholesterol in hippocampal neurons.
复制标题
海马神经元中内源性调节剂 24S-羟基胆固醇优先增强含有 GluN2B 的天然 NMDA 受体。
DOI：
10.1016/j.neuropharm.2018.12.028
复制
发表时间：
2019
影响因子：
4.7
通讯作者：
Mody,Istvan
中科院分区：
文献类型：
--
作者：
Wei,Xiaofei;Nishi,Toshiya;Kondou,Shinichi;Kimura,Haruhide;Mody,Istvan
24 S-羟基胆固醇（24 HC）是胆固醇在大脑中的主要代谢分解产物。在其对神经元的其他作用中，24 HC调节N-甲基-d-天冬氨酸（NMDA或GluN）受体，但我们对这一机制的理解很差。我们使用全细胞膜片钳记录和各种药理学方法在小鼠脑切片记录孤立的NMDA受体介导的（INMDA）紧张性和诱发性突触电流。24 HC（1 μ M）显著增强齿状回颗粒细胞的紧张性而非诱发性INMDA。INMDA含有GluN 2A和GluN 2B两种介导的成分。用PEAQX（GluN 2A拮抗剂）或Ro 25 -6981（GluN 2B拮抗剂）预孵育切片显著改变24 HC的INMDA调节潜力。Ro 25 -6981阻断了24 HC对紧张性INMDA的增强作用，而PEAQX预孵育则无影响。在胆固醇24-羟化酶（CYP 46 A1）基因敲除小鼠中，与WT形成鲜明对比的是，24 HC轻微降低颗粒细胞的紧张性INMDA。此外，24 HC对齿状回小白蛋白中间神经元（PV-IN）的紧张性INMDA没有影响，已知PV-IN表达与颗粒细胞不同的GluN亚基。两者合计，我们的研究结果显示了一个特定的增强含GluN 2B的NMDARs的24 HC，表明一种新的内源性途径，影响一个亚类的NMDARs关键参与皮层可塑性和许多神经和精神疾病。
24S-hydroxycholesterol (24HC) is the major metabolic breakdown product of cholesterol in the brain. Among its other effects on neurons, 24HC modulates N-methyl-d-aspartate (NMDA or GluN) receptors, but our understanding of this mechanism is poor. We used whole-cell patch clamp recordings and various pharmacological approaches in mouse brain slices to record isolated NMDAR-mediated (INMDA) tonic and evoked synaptic currents. 24HC (1 μΜ) significantly enhanced tonic, but not evoked, INMDA of dentate gyrus granule cells. The INMDA had both GluN2A and GluN2B-mediated components. Preincubation of the slices with PEAQX (a GluN2A antagonist) or Ro25-6981 (a GluN2B antagonist) dramatically changed the INMDAmodulatory potential of 24HC. Ro25-6981 blocked the enhancing effect of 24HC on tonic INMDA, while preincubation with PEAQX had no effect. In cholesterol 24-hydroxylase (CYP46A1) knockout mice, in sharp contrast to WT, 24HC slightly decreased the tonic INMDAof granule cells. Furthermore, 24HC had no effect on tonic INMDAof dentate gyrus parvalbumin interneurons (PV-INs), known to express different GluN subunits than granule cells. Taken together, our results revealed a specific enhancement of GluN2B-containing NMDARs by 24HC, indicating a novel endogenous pathway to influence a subclass of NMDARs critically involved in cortical plasticity and in numerous neurological and psychiatric disorders.