Dopamine depletion weakens direct pathway modulation of SNr neurons.

ABSTRACT

Neurons in the substantia nigra reticulata (SNr) transmit information about basal ganglia output to dozens of brain regions in thalamocortical and brainstem motor networks. Activity of SNr neurons is regulated by convergent input from upstream basal ganglia nuclei, including GABAergic inputs from the striatum and the external globus pallidus (GPe). GABAergic inputs from the striatum convey information from the direct pathway, while GABAergic inputs from the GPe convey information from the indirect pathway. Chronic loss of dopamine, as occurs in Parkinson's disease, disrupts the balance of direct and indirect pathway neurons at the level of the striatum, but the question of how dopamine loss affects information propagation along these pathways outside of the striatum is less well understood. Using a combination of in vivo and slice electrophysiology, we find that dopamine depletion selectively weakens the direct pathway's influence over neural activity in the SNr due to changes in the decay kinetics of GABA-mediated synaptic currents. GABAergic signaling from GPe neurons in the indirect pathway was not affected, resulting in an inversion of the normal balance of inhibitory control over basal ganglia output through the SNr. These results highlight the contribution of cellular mechanisms outside of the striatum that impact the responses of basal ganglia output neurons to the direct and indirect pathways in disease.