Chemogenetic Manipulation of the Subthalamic Nucleus-Substantia Nigra Pars Reticulata Pathway Promotes Recovery in HemiParkinsonian Rat Models

Abstract

Motor control through the basal ganglion is mediated primarily thought two pathways, the direct and indirect pathways. The indirect pathway functions in opposition to the direct pathway, balancing excitatory and inhibitory control over motor movement. In Parkinsons disease, the indirect pathway is thought to suppress movements through excessive excitation of inhibitory neurons within the globus pallidus internus and substantia nigra pars reticulata. In an attempt to restore this balance, we induced the expression of GAD65 in glutamatergic subthalamic neurons to enable the co-release of GABA. Previous studies indicated co-expression of GABA with glutamate reduces glutamate excitability and might restore balance to the network. Indeed, we observed a reduction in post-lesional amphetamine-induce rotations in 6OHDA lesioned rats co-transduced with GAD65 and excitatory DREADDs and activated by CNO. This study indicates rebalancing inhibitory and excitatory output from the subthalamic nucleus can have a positive effect on motor outcome.