Loss of nigral excitation of cholinergic interneurons contributes to parkinsonian motor impairments

Progressive loss of dopamine inputs in Parkinson?s disease leads to imbalances in coordinated signaling of dopamine and acetylcholine (ACh) in the striatum, which is thought to contribute to parkinsonian motor symptoms. As reciprocal interactions between dopamine inputs and cholinergic interneurons (ChIs) control striatal dopamine and ACh transmission, we examined how partial dopamine depletion in an early-stage mouse model for Parkinson?s disease alters nigral regulation of cholinergic activity. We found region-specific alterations in how remaining dopamine inputs regulate cholinergic excitability that differ between the dorsomedial (DMS) and dorsolateral (DLS) striatum. Specifically, we found that dopamine depletion downregulates metabotropic glutamate receptors (mGluR1) on DLS ChIs at synapses where dopamine inputs co-release glutamate, abolishing the ability of dopamine inputs to drive burst firing. This loss underlies parkinsonian motor impairments, as viral rescue of mGluR1 signaling in DLS ChIs was sufficient to restore circuit function and attenuate motor deficits in early-stage parkinsonian mice.

Automated summary

Progressive loss of dopamine inputs in Parkinson's disease leads to imbalances in coordinated signaling of dopamine and acetylcholine in the striatum, contributing to motor symptoms. Examining how partial dopamine depletion affects nigral regulation of cholinergic activity in an early-stage Parkinson's disease mouse model, revealed region-specific alterations in how remaining dopamine inputs regulate cholinergic excitability in the dorsomedial and dorsolateral striatum. Specifically, dopamine depletion downregulates metabotropic glutamate receptors on DLS ChIs, abolishing the ability of dopamine inputs to drive burst firing, leading to motor impairments in Parkinson's disease.