Calcium-based synaptic and structural plasticity link pathological activity to synaptic reorganization in Parkinson's disease.

Abstract

Motor symptoms of Parkinson's disease (PD) are associated with dopaminergic neuronal loss. Widespread synaptic reorganization and neural activity changes, including exaggerated beta oscillations and bursting, follow dopamine depletion (DD) of the basal ganglia (BG). Our computational model examines DD-induced neural activity changes and synaptic reorganization in the BG subcircuit comprising the subthalamic nucleus and globus pallidus externus. Calcium-dependent synaptic and structural plasticity mechanisms were incorporated, allowing neural activity to alter network topology. We show how hyperactivity of indirect pathway striatal projection neurons (iMSN) can induce synaptic connectivity changes consistent with PD animal models. Our results suggest that synaptic reorganization following DD results from a series of homeostatic calcium-based synaptic changes triggered by iMSN hyperactivity. While this structural plasticity functions as a compensatory mechanism in the cascade of changes following elevated iMSN input from striatal DD, it may become compromised if iMSN and cortical inputs show substantial bursting activity.