Persistent sodium current and its role in epilepsy

Abstract

Sodium currents are essential for the initiation and propagation of neuronal firing. Alterations of sodium currents can lead to abnormal neuronal activity, such as occurs in epilepsy. The transient voltage-gated sodium current mediates the upstroke of the action potential. A small fraction of sodium current, termed the persistent sodium current (I(NaP)), fails to inactivate significantly, even with prolonged depolarization. I(NaP) is activated in the subthreshold voltage range and is capable of amplifying a neuron's response to synaptic input and enhancing its repetitive firing capability. A burgeoning literature is documenting mutations in sodium channels that underlie human disease, including epilepsy. Some of these mutations lead to altered neuronal excitability by increasing I(NaP). This review focuses on the pathophysiological effects of I(NaP) in epilepsy.

FIGURE 1

A. Left—Schematic of persistent sodium current traversing a channel with incomplete (impaired) inactivation, as likely occurs in many epilepsy-related sodium channel mutations. Right—Current traces depicting the fast transient sodium current (downward spike) and persistent sodium current, reflecting the long-lasting increase in a small fraction of sodium current that can influence repetitive firing, synaptic integration, and threshold for action potential generation (reprinted with permission from J Clin Invest[reference 14]).B. Current clamp record of a plateau potential, mediated by persistent sodium current, in a layer V pyramidal neuron with potassium and calcium currents blocked. The sustained, depolarizing plateau potential long outlasts the brief current pulse (lower trace). The gradual decline of the plateau and eventual return of regenerative action potentials implies a very slow recovery of sodium channels from fast inactivation (reprinted with permission from J Neurophysiol[reference 41]).C–E. Persistent sodium current demonstrated in current clamp (panel C) and single-electrode ramp voltage-clamp (panels D and E) recordings from a single layer V neocortical neuron. In panels C and D, upper traces are voltage and lower traces are current. Panel C shows voltage responses to 200-millisecond hyperpolarizing (traces 1) and depolarizing current pulses (traces 2 and 3). At subthreshold voltages and voltages traversed by spike afterpotentials during repetitive firing (indicated by lines b and c, respectively), persistent inward current is generated (points b and c in panel D). Panel E shows current traces in response to ramp voltage commands (not shown), superimposed on a current–voltage plot. With TTX application, this rectification is eliminated, verifying that the inward current is mediated by voltage-sensitive sodium channels (adapted with permission from Brain Res[reference 20]).