Mechanisms of resurgent Na+ current in Purkinje neurons

描述（申请人提供）：小脑浦肯野神经元是一种特殊的神经元，它的自发放电频率高达50 Hz，即使在没有突触输入的情况下也存在。它们还表达一种独特的电压门控河豚毒素（TTX）敏感性钠电流，称为复活钠电流（拉曼和比恩，1997）缺乏电压门控钠通道Nav1.6的突变小鼠的浦肯野神经元不显示复苏电流，这表明Nav1.6是产生这种电流所必需的。这些小鼠还具有破坏的浦肯野神经元放电和共济失调表型（拉曼等人，1997年）。这些观察结果表明，复苏电流是重要的维持放电率在浦肯野神经元，和正常的浦肯野放电是重要的运动协调。复活电流的机制尚不清楚;然而，其维持所需的成分似乎是浦肯野神经元固有的，因为表达Nav1.6的其他细胞不携带复活电流。电生理学和药理学方法的组合将用于急性分离的浦肯野神经元，以解决复活电流的分子机制，包括钠通道β亚基的作用和钠通道的翻译后修饰。此外，实验将解决潜在的调制复活电流小脑神经递质。本研究的总体目标是确定自发放电和正常运动协调的基础浦肯野神经元的内在属性之间的功能关系。

DESCRIPTION (provided by applicant): Cerebellar Purkinje neurons are unusual because of their high spontaneous firing rate of about 50 Hz that is present even in the absence of synaptic input They also express a unique voltage-gated tetrodotoxin (TTX)-sensitive sodium current called resurgent sodium current (Raman and Bean, 1997) Purkinje neurons of mutant mice that lack the voltage-gated sodium channel Nav1.6 do not exhibit resurgent current, suggesting that Nav1.6 is necessary for the generation of this current These mice also have disrupted Purkinje neuron firing and an ataxic phenotype (Raman et al., 1997). These observations suggest that resurgent current is important for maintaining the firing rate in Purkinje neurons, and that normal Purkinje firing is important for motor coordination. The mechanisms of resurgent current are unknown; however, the components needed for its maintenance appear to be intrinsic to Purkinje neurons since other cells expressing Nav1.6 do not carry resurgent current. A combination of eleetrophysiological and pharmacological approaches will be used on acutely dissociated Purkinje neurons to address the molecular mechanisms of resurgent current, including the role of sodium channel beta subunits and post-translational modifications to the sodium channel. In addition, experiments will address the potential modulation of resurgent current by cerebellar neurotransmitters. The overall goal of this research is to identify the functional relationship between the intrinsic properties of Purkinje neurons that underlie spontaneous firing and normal motor coordination.