Although it is well known that high-frequency stimulation (HFS) of the subthalamic nucleus (STN) alleviates the cardinal symptoms of Parkinson's disease, the underlying mechanisms are not fully understood. We investigated the effect of stimulation from low to high frequencies on rat STN neurons in naive and dopamine-depleted slices using whole-cell, current-clamp techniques and on-line artifact suppression. Stimulation at 10 Hz evoked 10 Hz single spikes but did not significantly modify ongoing STN activity. In contrast, at therapeutically relevant frequencies (80-185 Hz), stimulation had a dual effect: it fully suppressed STN spontaneous activity and generated a robust pattern of recurrent bursts of spikes, with each spike being time-locked to a stimulus pulse. Neither the suppression of spontaneous activity nor the generation of spikes was prevented by the antagonists of the metabotropic and ionotropic receptors of glutamate and gamma-aminobutyric acid. Tetrodotoxin, the Na+ channel blocker, suppressed all HFS-evoked spikes, whereas nifedipin, an L-type Ca2+-channel blocker, abolished the membrane oscillations underlying bursts. Therefore, we conclude that HFS drives the STN neuronal activity by directly activating the neuronal membrane. We suggest that this pattern may remove the deleterious activity of the basal ganglia network in the parkinsonian state and drive target neurons to a high-frequency state of activity, dependent on the characteristics of STN efferent synapses and resonant properties of target membranes.

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