Modulation of premotor cortex excitability mitigates the behavioral and electrophysiological abnormalities in a Parkinson’s Disease Mouse Model

The subthalamic nucleus (STN) is important in halting ongoing behaviors, referred to as stop-signal responses. The prefrontal regions innervating the STN exhibit increased activity during the stop-signal responses, and optogenetic activation of these neurons inhibits impulsive actions in rodents. High-frequency electrical stimulation of the STN effectively treats motor symptoms of Parkinson’s disease (PD), yet its underlying circuit mechanisms are unclear. Here, we investigated the involvement of STN-projecting premotor (M2) neurons in PD mouse models and the impact of deep brain stimulation targeting the STN (DBS-STN). We found that M2 neurons exhibited enhanced burst firing and synchronous oscillations in the PD mouse model. Remarkably, high-frequency stimulation of STN-projecting M2 neurons, simulating antidromic activation, during DBS-STN relieved motor symptoms and hyperexcitability. These changes were attributed to reduced firing frequency vs. current relationship through normalized hyperpolarization-activated inward current (Ih). The M2 neurons in the PD model mouse displayed increased Ih, which was reversed by high-frequency stimulation. Additionally, the infusion of ZD7288, an HCN channel blocker, into the M2 replicated the effects of high-frequency stimulation. In conclusion, our study unveils excessive excitability and suppressive motor control through M2-STN synapses in the PD mouse model. Antidromic excitation of M2 neurons during deep brain stimulation of the STN alleviates this suppression, thereby improving motor impairment. These findings provide insights into the circuit-level dynamics underlying deep brain stimulation’s therapeutic effects in PD. Targeting M2-STN synapses may be useful for future therapeutic strategies. Significance Statement Our study provides insight into the mechanisms driving motor impairment in Parkinson’s disease (PD) and the therapeutic efficacy of deep brain stimulation (DBS). By elucidating the role of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in modulating the hyperexcitability of M2 neurons, we identify potential targets for future PD treatment strategies. Understanding the excessive excitability and suppressive motor control through M2-STN synapses in PD mouse models contributes to our knowledge of circuit-level dynamics underlying DBS effects. These findings have significant implications for improving motor symptoms and advancing the development of more precise and effective interventions for PD patients. ### Competing Interest Statement The authors have declared no competing interest.