Abstract Details

Title Striatal Acetylcholine and Dopamine are Necessary for Motor Function in Parkinsonism

Topic Movement Disorders

Presentation(s) P5 - Poster Session 5 (5:30 PM-6:30 PM)

Poster/Presentation
Number 10-001

Objective We hypothesized that dopamine deficiency at clinically-relevant levels reduces striatal acetylcholine content and cholinergic interneuron firing.

Background Genetic and acquired forms of Parkinsonism in children cause motor and non-motor impairments by modifying dopamine and acetylcholine availability. An assumption that increased acetylcholine availability accompanies dopamine deficiency is based on the outcome of pharmacological treatments dating back to the 1950’s and few measurements in animals that were critically depleted of dopamine.

Design/Methods We performed integrated behavioral, electrophysiological, and molecular experiments in genetically-modified Slc6a3^DTR/+ mice (n=243), where diphtheria toxin (50µg/kg, i.m.) specifically ablates dopamine-producing cells, while sparing sham-injected mice. Rotarod assessed motor dysfunction, electrophysiology examined striatal cholinergic-interneuron (ChI) activity, HPLC determined tissue concentration of dopamine and acetylcholine, and the RiboTag method examined cell-type and brain region specific changes in the transcription of hyperpolarization-activated cation (HCN) channel subunits and choline acetyltransferase (ChAT), the enzyme required for acetylcholine synthesis. Chat^Cre x Rosa26-fs-tdTomato mice were used to visualize the sparse population of striatal ChIs by fluorescent microscopy.

Results 30-day-old Slc6a3^DTR/+ x RiboTag (B6N.129-Rpl22^tm1.1Psam/J) x Chat^Cre x Rosa26-fs-tdTomato mice experienced a progressive and clinically-relevant reduction (~60%) in striatal dopamine and acetylcholine content and the expression of ChAT. Motor dysfunction was dependent on both acetylcholine and dopamine availability. HCN channel subunit expression decreased ChI activity, which paradoxically increased in response to dopamine released from residual axons.

Conclusions

We present several lines of evidence to demonstrate that dopamine deficiency at clinically relevant levels reduces striatal acetylcholine, contrary to long-held assumptions. The reduction in acetylcholine availability is to a lesser degree than dopamine so that the increase in acetylcholine content, relative to dopamine, contributes to the clinical symptoms of parkinsonism and may lead to L-dopa-induced dyskinesias. The data implicate HCN channels on striatal acetylcholine interneurons as a novel treatment target for motor dysfunction in Parkinsonism.

Authors/Disclosures
Nigel S. Bamford, MD (Yale University) PRESENTER	No disclosure on file
	No disclosure on file
	No disclosure on file

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