Conveyance of cortical pacing for parkinsonian tremor-like hyperkinetic behavior by subthalamic dysrhythmia

Parkinson’s disease is characterized by both hypokinetic and hyperkinetic symptoms. While increased subthalamic burst discharges have a direct causal relationship with the hypokinetic manifestations (e.g., rigidity and bradykinesia), the origin of the hyperkinetic symptoms (e.g., resting tremor and propulsive gait) has remained obscure. Neuronal burst discharges are presumed to be autonomous or less responsive to synaptic input, thereby interrupting the information flow. We, however, demonstrate that subthalamic burst discharges are dependent on cortical glutamatergic synaptic input, which is enhanced by A-type K+ channel inhibition. Excessive top-down-triggered subthalamic burst discharges then drive highly correlative activities bottom-up in the motor cortices and skeletal muscles. This leads to hyperkinetic behaviors such as tremors, which are effectively ameliorated by inhibition of cortico-subthalamic AMPAergic synaptic transmission. We conclude that subthalamic burst discharges play an imperative role in cortico-subcortical information relay, and they critically contribute to the pathogenesis of both hypokinetic and hyperkinetic parkinsonian symptoms. [Display omitted] •A-type K+ channels prominently modulate cortico-subthalamic synaptic transmission•Cortico-subthalamic glutamatergic input triggers burst firing in the subthalamic nucleus•Exaggerated bursts induce coherent oscillations in the motor cortex and skeletal muscles•Erroneous re-entrant information relay leads to parkinsonian hyperkinetic behaviors The origin of parkinsonian tremors remains obscure. In opposition to the conventional view that neuronal burst activities are autonomous, Huang et al. show that subthalamic burst discharges are dependent on input from the motor cortex, causing erroneous re-entrant information relays from cortico-subthalamic to pallido-thalamocortical loops and thus parkinsonian tremors.