Differential synaptic depression mediates the therapeutic effect of deep brain stimulation

Deep brain stimulation (DBS) effectively treats drug-resistant neurological and psychiatric disorders, yet its mechanisms remain unclear. Here we show that high-frequency DBS of the subthalamic nucleus (STN), a common target for Parkinson's disease (PD), activates afferent axons while inhibiting STN neurons. These contrasting presynaptic and postsynaptic effects arise from a decrease in local neurotransmitter release with a larger decrease in glutamate than GABA, shifting the excitation/inhibition balance toward inhibition. Chemogenetic inhibition, but not excitation, of STN neurons mimics the therapeutic effects of DBS in 6-OHDA-lesioned PD mice. Acute and chronic bilateral chemogenetic STN inhibition restores motor function in a progressive PD mouse model. These findings suggest that inhibition of STN, caused by differential depression of glutamatergic and GABAergic synapses, is a key mechanism of therapeutic DBS. 'Chemogenetic DBS', direct chemogenetic inhibition of postsynaptic neurons, may offer a less invasive and more affordable alternative to electrical DBS for PD and other neurological disorders.