Mechanisms of resurgent Na+ current in Purkinje neurons

描述(由申请人提供)：小脑Purkinje神经元是不寻常的，因为它们的高自发放电速率约50赫兹，即使在没有突触输入的情况下，它们也表达一种独特的电压门控河豚毒素(TTX)敏感的钠电流，称为复发性钠电流(Raman和Bean，1997)。这些观察结果表明，复活电流对维持浦肯野神经元的放电率很重要，而正常的浦肯野放电对运动协调很重要。复苏电流的机制尚不清楚；然而，维持电流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苏电流。电生理和药理学方法的结合将用于急性分离的浦肯野神经元，以解决复苏电流的分子机制，包括钠通道β亚基的作用和钠通道的翻译后修饰。此外，实验将解决小脑神经递质对复活电流的潜在调制。这项研究的总体目标是确定作为自发放电基础的浦肯野神经元的内在属性与正常运动协调之间的功能关系。

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.