A persistent little current with a big impact on epileptic firing.

Commentary Inward sodium current through specific membrane proteins (channels) constitutes the currency of neuronal firing. The transient voltage-dependent sodium current, I Na , with its all-or-none threshold behavior and rapid activation and inactivation, is responsible for the upstroke of the action potential. A smaller but longer lasting sodium current, carried through the same channels, comprises the persistent sodium current (I NaP). I NaP is activated in the subthreshold voltage range and serves to augment excitability by adding to other currents that depolarize the cell (1). Though minute by comparison with the transient sodium current (comprising only a small percentage of the peak I Na), I NaP does not inactivate and persists for hundreds of milliseconds; these biophysical features allow the depolarization engendered by I NaP to mediate more sustained neuronal excita-tion. For example, owing to its long-duration kinetics and activation at voltages traversed during interspike intervals in trains of action potentials, I NaP lowers the threshold for action potential generation, sustains repetitive firing, and enhances depolarizing synaptic currents (2). These excitability enhancing effects of I NaP suggest that it can facilitate epileptic burst firing. I NaP is present in neurons in a wide variety of brain areas and across mammalian species; it has emerged as a critical player in the modulation of neuronal firing in both normal and pathological states (3). Mutations in genes coding for sodium channel subunits have been identified in several epilepsy syndromes, including Dravet syndrome and generalized epilepsy with febrile seizures plus (4, 5). Although many other molecular mechanisms are involved in epilepsies caused by sodium channel mutations (e.g., loss-of-function of SCN1A (4,5)), some epilepsy patients with gain-of-function mutations in the sodium channel gene SCN1A (6), and epileptic mice with Scn2a mutations (7), have been reported to express increased I NaP as a pathophysiological consequence. Furthermore, a growing number of antiepileptic drugs appear to function, at least in part, by reducing I NaP (8, 9). Here, Chen and colleagues expand the potential roles of I NaP to acquired epilepsy, in this case, temporal lobe epilepsy (TLE). Using a well-recognized animal model of TLE, induced by pilocarpine, the authors examine the role of I NaP in the bursting behavior of hippocampal CA1 pyramidal neurons. Under normal conditions, CA1 neurons do not burst. However , in chronic epilepsy models, many CA1 neurons exhibit bursting behavior, that is, generate multiple action potentials in response to a stimulus that ordinarily …