Reduced Thalamic Excitation to Motor Cortical Pyramidal Tract Neurons in a Mouse Model of Parkinsonism

Abstract

Degeneration of midbrain dopaminergic (DA) neurons causes a reduced motor output from the primary motor cortex (M1), underlying the motor symptoms of Parkinsons disease (PD). However, cellular and circuitry mechanisms of M1 dysfunction in PD remain undefined. Using multidisciplinary approaches, we found that DA degeneration induces cell-subtype- and inputs-specific reduction of thalamic excitation to M1 pyramidal tract (PT) neurons. Physiological and anatomical analyses suggest that DA degeneration induces a loss of thalamocortical synapses to M1 PT neurons, resulting in an impaired thalamic driving of their activities. Moreover, we showed that the decreased thalamocortical connectivity are mediated by an excessive activation of NMDA receptors of M1 PT neurons. Further, the decreased thalamocortical transmission in parkinsonism can be rescued by chemogenetically suppressing basal ganglia outputs. Together, our data suggest that the reduced motor cortical outputs in parkinsonism are not only an immediate consequence of basal ganglia inhibition but also involves specific local circuitry adaptations within M1. This study reveals novel insight in the pathophysiology of parkinsonian motor deficits.

Motor Cortical Neuronal Hyperexcitability Associated with α-Synuclein Aggregation

“…This model assumes that cortical microcircuits remain intact in parkinsonian state and that cortical hypofunction is an instant effect of the exaggerated suppression of thalamus by the basal ganglia. However, converging evidence from recent studies suggest that the motor cortex shows intrinsically disrupted connection and function in animal models of parkinsonism that can play a major role in cortical pathophysiology of PD (Chu, 2024). These local cortical changes include altered dendritic spine dynamics and density of cortical pyramidal neurons and reduced thalamic axonal markers in the primary motor cortex (M1) of both parkinsonian monkeys and rodents (Guo et al, 2015;Villalba et al, 2019;Chen et al, 2023).…”