Neurotrophin-dependent regulation of voltage-gated sodium channels

摘要 神经精神障碍被认为是由大脑可塑性的复杂变化引起的。最近的证据 指向离子通道复合体，作为细胞的可塑性中心，赋予疾病脆弱性或保护性 取决于渠道监管状态。在伏核(NAC)的中棘神经元(MSN)中， 作为一种高度脆弱的细胞亚型，神经适应性改变的内在放电是由神经营养因子介导的 脑源性神经营养因子/原肌球蛋白受体激酶B(TrkB)信号传导。 然而，分子 人们对这些变化发生的机制仍知之甚少。 MSN的本征激发依赖于电压门控Na(Nav)大分子络合物的完整性 通道Nav1.6及其辅助调节性成纤维细胞生长因子14(FGF14)，并受 糖原合成酶激酶3(GSK3)β，脑源性神经营养因子/TrkB信号的下游效应因子。在这里，我们提供 令人兴奋的新证据表明，NAV1.6、FGF14和GSK3β是下游的大分子信号复合体 BDNF/TrkB对MSNS神经元可塑性至关重要。使用一系列体外和细胞分析，细胞成像， 和电生理，我们证明了Nav1.6通道的稳定性、磷酸化和功能活性是 与脑源性神经营养因子水平和激酶活性成正比，因此低水平的 BDNF预测复原力和 高水平介导神经元放电变化所产生的易感表型。我们将进行一次全面的 结合药理学和病毒的生物物理、生化和电生理研究的范围 基于载体的体内基因转移方法评价BDNF/TrkB信号对大分子的影响 日本NAV1.6通道的组成(目标1)、亚细胞靶向(目标2)和功能特性(目标3) MSN的神经适应性可塑性的背景。这些研究的结果可能会导致 通过分子途径研究神经精神疾病易感性的生物标志物 在相关的实验模型中，生物精神病学是一个非常感兴趣的领域。

ABSTRACT Neuropsychiatric disorders are thought to arise from complex changes of brain plasticity. Recent evidence points toward ion channel complexes as cellular hubs of plasticity that confer disease vulnerability or protection depending on the channel regulatory state. In medium spiny neurons (MSNs) in the nucleus accumbens (NAc), a subtype of highly vulnerable cells, neuroadaptive changes in intrinsic firing are mediated by neurotrophin brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) signaling. Yet, the molecular mechanisms by which these changes occur are still poorly understood. Intrinsic firing in MSN relies on the integrity of the macromolecular complex of the voltage-gated Na+ (Nav) channel Nav1.6 and its accessory regulatory fibroblast growth factor 14 (FGF14) and is subject to regulation by glycogen synthase kinase 3 (GSK3) β, a downstream effector of BDNF/TrkB signaling. Here, we provide exciting new evidence for the Nav1.6, FGF14 and GSK3β as a macromolecular signaling complex downstream of BDNF/TrkB critical for MSNs neuronal plasticity. Using an array of in vitro and in cell assays, cell imaging, and electrophysiology, we show that stability, phosphorylation and functional activity of the Nav1.6 channel are proportional to the level of BDNF and the kinase activity, whereby low level of BDNF predicts resilience and high level mediates a susceptible phenotype conferred by changes in neuron firing. We will conduct a full range of biophysical, biochemical and electrophysiological studies combined with pharmacological and viral vector-based in vivo gene transfer methods to evaluate the impact of BDNF/TrkB signaling on macromolecular composition (Aim 1), subcellular targeting (Aim 2) and functional properties (Aim 3) of the Nav1.6 channel in the context of neuroadaptive plasticity of MSNs. Outcomes of these studies could potentially lead to the development of biomarkers of susceptibility to neuropsychiatric disorders by investigating molecular pathways in relevant experimental models, an area of great interest for biological psychiatry.