Reduced thalamic excitation to motor cortical pyramidal tract neurons in parkinsonism

• DOI: 10.1126/sciadv.adg3038
• Publication Date: 2023-08-23T17:58:33Z
• Authors: Liqiang Chen; Samuel Daniels; Rachel Dvorak; Hong-Yuan Chu
• Keywords: Motor Neurons; 0301 basic medicine; Mice; 03 medical and health sciences; 0302 clinical medicine; Parkinsonian Disorders; Pyramidal Tracts; Animals; Parkinson Disease; Receptors, N-Methyl-D-Aspartate; Basal Ganglia; Neuroscience

Degeneration of midbrain dopaminergic (DA) neurons alters the connectivity and functionality of the basal ganglia-thalamocortical circuits in Parkinson’s disease (PD). Particularly, the aberrant outputs of the primary motor cortex (M1) contribute to parkinsonian motor deficits. However, cortical adaptations at cellular and synaptic levels in parkinsonism remain poorly understood. Using multidisciplinary approaches, we found that DA degeneration induces cell subtype– and input-specific reduction of thalamic excitation to M1 pyramidal tract (PT) neurons. At molecular level, we identified that N -methyl- d -aspartate (NMDA) receptors play a key role in mediating the reduced thalamocortical excitation to PT neurons. At circuit level, we showed that the reduced thalamocortical transmission in parkinsonian mice can be rescued by chemogenetically suppressing basal ganglia outputs. Together, our data suggest that cell subtype– and synapse-specific adaptations in M1 contribute to altered cortical outputs in parkinsonism and are important aspects of PD pathophysiology.