EFFECTS OF OPTOGENETIC AND ELECTRIC DBS ON THE STN AND ITS SYNAPTIC TARGETS

Parkinson’s disease (PD) is a progressive movement disorder caused by degeneration of dopaminergic neurons. Deep brain stimulation (DBS) is offered to PD patients when dopamine replacement therapy becomes ineffective. Patients undergoing DBS receive continuous high-frequency electrical stimulation, most often in the subthalamic nucleus (STN). Although DBS is clinically successful, its neuronal and synaptic mechanisms remain unknown.
We applied high-frequency electrical (eDBS) and optogenetic (oDBS) stimulation to STN neurons in mice and obtained ex vivo and in vivo patch-clamp recordings to address the following questions: Can STN neurons sustain clinically relevant frequencies (up to 125 Hz)? And what is the effect of high-frequency stimulation of STN synaptic terminals in the external globus pallidus (GPe) and subtantia nigra reticulata (SNr)?
We demonstrate that high-frequency eDBS (100 and 125 Hz) reliably increases firing in most STN neurons, although it declines during ongoing stimulation. A subset of neurons failed to follow the full stimulation train, also at lower frequencies (40 and 80 Hz). Similar patterns were observed upon oDBS. Additionally, stimulation of STN terminals in the GPe and SNr at high frequencies (100–125 Hz), induced strong frequency-dependent synaptic depression, often resulting in complete synaptic failure upon sustained stimulation both in vivo and ex vitro.
DBS transiently drives high-frequency STN firing while progressively attenuating firing and inducing STN output synaptic depression. Thus, the therapeutic effect of DBS may be linked to a depletion of STN synapses onto its target nuclei in the basal ganglia.