Slowly inactivating sodium current (I(NaP)) underlies single-spike activity in rat subthalamic neurons

Abstract

One-half of the subthalamic nucleus (STN) neurons switch from single-spike activity to burst-firing mode according to membrane potential. In an earlier study, the ionic mechanisms of the bursting mode were studied but the ionic currents underlying single-spike activity were not determined. The single-spike mode of activity of STN neurons recorded from acute slices in the current clamp mode is TTX-sensitive but is not abolished by antagonists of ionotropic glutamatergic and GABAergic receptors, blockers of calcium currents (2 mM cobalt or 40 microM nickel), or intracellular Ca(2+) ions chelators. Tonic activity is characterized by a pacemaker depolarization that spontaneously brings the membrane from the peak of the afterspike hyperpolarization (AHP) to firing threshold (from -57.1 +/- 0.5 mV to -42.2 +/- 0.3 mV). Voltage-clamp recordings suggest that the Ni(2+)-sensitive, T-type Ca(2+) current does not play a significant role in single-spike activity because it is totally inactivated at potentials more depolarized than -60 mV. In contrast, the TTX-sensitive, I(NaP) that activated at -54.4 +/- 0.6 mV fulfills the conditions for underlying pacemaker depolarization because it is activated below spike threshold and is not fully inactivated in the pacemaker range. In some cases, the depolarization required to reach the threshold for I(NaP) activation is mediated by hyperpolarization-activated cation current (I(h)). This was directly confirmed by the cesium-induced shift from single-spike to burst-firing mode which was observed in some STN neurons. Therefore, a fraction of I(h) which is tonically activated at rest, exerts a depolarizing influence and enables membrane potential to reach the threshold for I(NaP) activation, thus favoring the single-spike mode. The combined action of I(NaP) and I(h) is responsible for the dual mode of discharge of STN neurons.