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

• Published in: Cell reports (Cambridge) Vol. 35; no. 3; p. 109007
• Main Authors: Huang, Chen-Syuan, Wang, Guan-Hsun, Chuang, Hsiang-Hao, Chuang, Ai-Yu, Yeh, Jui-Yu, Lai, Yi-Chen, Yang, Ya-Chin
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.04.2021; Elsevier
• Subjects: 4-Aminopyridine - pharmacology; 6-Cyano-7-nitroquinoxaline-2,3-dione - pharmacology; A-type K+ channel; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid - pharmacology; Animals; basal ganglia network; brain oscillation; burst discharge; cortico-subcortical reentrant loop; cortico-subthalamic transmission; Excitatory Amino Acid Agonists - pharmacology; Excitatory Amino Acid Antagonists - pharmacology; Female; Globus Pallidus - drug effects; Globus Pallidus - metabolism; Globus Pallidus - physiopathology; glutamatergic transmission; Glutamic Acid - metabolism; Glutamic Acid - pharmacology; Humans; hyperdirect pathway; Hyperkinesis - metabolism; Hyperkinesis - physiopathology; Male; Membrane Potentials - drug effects; Mice; Mice, Inbred C57BL; motor control; Motor Cortex - drug effects; Motor Cortex - metabolism; Motor Cortex - physiopathology; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Muscle, Skeletal - physiopathology; Optogenetics - methods; Parkinson Disease, Secondary - metabolism; Parkinson Disease, Secondary - physiopathology; parkinsonian tremor; Rats; Rats, Wistar; Subthalamic Nucleus - drug effects; Subthalamic Nucleus - metabolism; Subthalamic Nucleus - physiopathology; Synapses - drug effects; Synapses - metabolism; Synapses - pathology; Synaptic Transmission; Tremor - metabolism; Tremor - physiopathology; glutamatergic transmission; basal ganglia network; A-type K+ channel; hyperdirect pathway; burst discharge; parkinsonian tremor; brain oscillation; cortico-subcortical reentrant loop; motor control; cortico-subthalamic transmission; A-type K(+) channel
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.109007

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.