High-frequency stimulation produces a transient blockade of voltage-gated currents in subthalamic neurons

Abstract

The effect of high-frequency stimulation (HFS) of the subthalamic nucleus (STN) was analyzed with patch-clamp techniques (whole cell configuration, current- and voltage-clamp modes) in rat STN slices in vitro. A brief tetanus, consisting of 100-micros bipolar stimuli at a frequency of 100--250 Hz during 1 min, produced a full blockade of ongoing STN activity whether it was in the tonic or bursting mode. This HFS-induced silence lasted around 6 min after the end of stimulation, was frequency dependent, could be repeated without alteration, and was not synaptically induced as it was still observed in the presence of blockers of ionotropic GABA and glutamate receptors or in the presence of cobalt at a concentration (2 mM) that blocks voltage-gated Ca(2+) channels and synaptic transmission. During HFS-induced silence, the following alterations were observed: the persistent Na(+) current (I(NaP)) was totally blocked (by 99%), the Ca(2+)-mediated responses were strongly reduced including the posthyperpolarization rebound (-62% in amplitude) and the plateau potential (-76% in duration), suggesting that T- and L-type Ca(2+) currents are transiently depressed by HFS, whereas the Cs(+)-sensitive, hyperpolarization-activated cationic current (I(h)) was little affected. Thus a high-frequency tetanus produces a blockade of the spontaneous activities of STN neurons as a result of a strong depression of intrinsic voltage-gated currents underlying single-spike and bursting modes of discharge. These effects of HFS, which are completely independent of synaptic transmission, provide a mechanism for interrupting ongoing activities of STN neurons.