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Abstract High-frequency deep brain stimulation (DBS) of subthalamic nucleus (STN) is an effective clinical therapy for Parkinson's disease (PD), but the underlying cellular and circuit mechanism remains unclear. Here we find a critical role of asynchronous release (AR) of GABA induced by high-frequency stimulation (HFS) at STN in the improvement of motor functions in dopamine-depleted (DD) mice. HFS at 130 Hz causes an initial inhibition followed by desynchronization of spiking activity of STN neurons, largely attributable to presynaptic GABA release. In contrast, low-frequency stimulation (LFS) at 20 Hz produces much weaker AR and a neglectable effect on spiking activity of STN neurons. Further experiments demonstrate that the activation of parvalbumin (PV) axons, but not non-PV axons, from external globus pallidus (GPe) is both necessary and sufficient for the therapeutic effect of DBS. A decrease in AR strength diminishes the high-frequency DBS effect, whereas an increase in AR strength enhances the effect of low-frequency DBS. Together, our results reveal a crucial role of asynchronous GABA release from GPe PV neurons in the improvement of motor functions under Parkinsonian conditions.
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