Mechanisms of resurgent Na+ current in Purkinje neurons

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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.