PDF(Pubmed)
Abstract：
The pathogenesis of schizophrenia is believed to involve combined dysfunctions of many proteins including microtubule-associated protein 6 (MAP6) and Kv3.1 voltage-gated K+ (Kv) channel, but their relationship and functions in behavioral regulation are often not known. Here we report that MAP6 stabilizes Kv3.1 channels in parvalbumin-positive (PV+ ) fast-spiking GABAergic interneurons, regulating behavior. MAP6-/- and Kv3.1-/- mice display similar hyperactivity and avoidance reduction. Their proteins colocalize in PV+ interneurons and MAP6 deletion markedly reduces Kv3.1 protein level. We further show that two microtubule-binding modules of MAP6 bind the Kv3.1 tetramerization domain with high affinity, maintaining the channel level in both neuronal soma and axons. MAP6 knockdown by AAV-shRNA in the amygdala or the hippocampus reduces avoidance or causes hyperactivity and recognition memory deficit, respectively, through elevating projection neuron activity. Finally, knocking down Kv3.1 or disrupting the MAP6-Kv3.1 binding in these brain regions causes avoidance reduction and hyperactivity, consistent with the effects of MAP6 knockdown. Thus, disrupting this conserved cytoskeleton-membrane interaction in fast-spiking neurons causes different degrees of functional vulnerability in various neural circuits.
摘要：
精神分裂症的发病机制被认为涉及许多蛋白质的联合功能障碍，包括微管相关蛋白6（MAP6）和Kv3.1电压门控K（Kv）通道，但是它们在行为调节中的关系和功能通常是未知的。在这里，我们报告说，MAP6稳定了小白蛋白阳性（PV）快速尖峰GABA能中间神经元中的Kv3.1通道，规范行为。MAP6-/-和Kv3.1-/-小鼠表现出相似的多动和回避减少。它们的蛋白质共定位在PV中间神经元中，MAP6缺失显着降低了Kv3.1蛋白质水平。我们进一步表明，MAP6的两个微管结合模块以高亲和力结合Kv3.1四聚化域，维持神经元体细胞和轴突的通道水平。通过杏仁核或海马中的AAV-shRNA敲除MAP6减少回避或导致多动症和识别记忆缺陷，分别,通过提升投影神经元的活动。最后,击倒Kv3.1或破坏这些脑区的MAP6-Kv3.1结合会导致回避减少和多动症，与MAP6敲低的效果一致。因此，破坏快速尖峰神经元中这种保守的细胞骨架-膜相互作用会导致各种神经回路中不同程度的功能脆弱性。
