Objective/Rationale:
The role of striatal cholinergic interneurons (ChIs) in Parkinson’s disease and side effects of treatment like levodopa-induced dyskinesia (LID) have been poorly studied. We have recently shown an important role of ChIs in LID in pre-clinical models of LID. ChIs have profound influence on other striatal cells that receive dopaminergic input, but represent only 2-5% of the total striatal neurons. Therefore, it has been difficult to study this population of neurons. We propose to employ a new technique involving genetically altered pre-clinical models to modulate ChI activity, specifically to study their function in PD models.
Project Description:
We will utilize a genetic pre-clinical model and viral vectors that can deliver the gene into the brain to target expression of ion channel gene specifically in the ChIs. By implanting optic fibers that can deliver light to the striatal area, we can selectively suppress the activities of ChIs in the striatum. A light generated from an optic fiber implant alters the channel activity and suppresses neuronal activity. We will test if such alteration of ChI activity will prevent and attenuate LID. Alternative means of killing ChIs specifically by a viral vector mediated delivery of toxic genes will also be employed as a complementary approach. These experiments will solidify the importance of ChIs in parkinsonian pre-clinical models and their role in LID beyond our previous studies using pharmacological agents and anatomical identification.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
LID is one of the major complications of current PD therapy. Understanding molecular mechanisms of LID is critical in devising new therapies for LID.
Anticipated Outcome:
This project will tell us if ChIs play an important role in the development and expression of LID. Our results will focus our attention to a cell type in the brain that has not been utilized recently for PD therapy. This study will provide a strong motivation and direction for novel therapeutic approaches for PD.
Final Outcome
The present study was undertaken to provide anatomically specific evidence for the role of striatal cholinergic interneurons by killing them prior to initiation of levodopa treatment and determining if it prevents levodopa-induced dyskinesia. We employed a novel approach to kill striatal cholinergic interneurons (ChIs) via Cre-dependent viral expression of the active subunit of diphtheria toxin A subunit (DT-A) in a hemiparkinsonian transgenic model. This model expresses Cre recombinase under control of the choline acetyltransferase promoter and selectively activates the toxin when AAV is introduces. We showed that Cre recombinase-mediated DT-A expression selectively eliminated ChIs when injected into striatum. The depletion of ChIs markedly attenuated levodopa-induced dyskinesia without compromising the therapeutic efficacy of levodopa. These results provide evidence that ChIs play a key and selective role in dyskinesia and that strategies to reduce striatal cholinergic tone may represent a promising approach to decreasing levodopa-induced motor complications in Parkinson’s disease.
Presentations & Publications
Won L, Ding Y, Singh P, Kang UJ. Striatal cholinergic cell ablation attenuates L-DOPA induced dyskinesia in Parkinsonian mice. J Neurosci 2014 (in press)
February 2014