Striatal cholinergic cell ablation attenuates L-DOPA induced dyskinesia in Parkinsonian mice

J Neurosci. 2014 Feb 19;34(8):3090-4. doi: 10.1523/JNEUROSCI.2888-13.2014.


3,4-Dihydroxyphenyl-L-alanine (L-DOPA)-induced dyskinesia (LID) is a debilitating side effect of long-term dopamine replacement therapy in Parkinson's Disease. At present, there are few therapeutic options for treatment of LID and mechanisms contributing to the development and maintenance of these drug-induced motor complications are not well understood. We have previously shown that pharmacological reduction of cholinergic tone attenuates the expression of LID in parkinsonian mice with established dyskinesia after chronic L-DOPA treatment. The present study was undertaken to provide anatomically specific evidence for the role of striatal cholinergic interneurons by ablating them before initiation of L-DOPA treatment and determining whether it decreases LID. We used a novel approach to ablate striatal cholinergic interneurons (ChIs) via Cre-dependent viral expression of the diphtheria toxin A subunit (DT-A) in hemiparkinsonian transgenic mice expressing Cre recombinase under control of the choline acetyltransferase promoter. We show that Cre recombinase-mediated DT-A ablation selectively eliminated ChIs when injected into striatum. The depletion of ChIs markedly attenuated LID without compromising the therapeutic efficacy of L-DOPA. These results provide evidence that ChIs play a key and selective role in LID and that strategies to reduce striatal cholinergic tone may represent a promising approach to decreasing L-DOPA-induced motor complications in Parkinson's disease.

Keywords: Parkinson's disease; behavior; cholinergic; diphtheria toxin; dyskinesia; striatum.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Antiparkinson Agents / toxicity*
  • Behavior, Animal / drug effects
  • DNA, Complementary / biosynthesis
  • DNA, Complementary / genetics
  • Denervation
  • Diphtheria Toxin / pharmacology
  • Dyskinesia, Drug-Induced / physiopathology
  • Dyskinesia, Drug-Induced / therapy*
  • Hydroxydopamines / toxicity
  • Image Processing, Computer-Assisted
  • Immunohistochemistry
  • Levodopa / toxicity*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neostriatum / cytology
  • Neostriatum / physiology*
  • Parasympathetic Nervous System / cytology
  • Parasympathetic Nervous System / physiology*
  • Parkinsonian Disorders / physiopathology
  • Parkinsonian Disorders / therapy*


  • Antiparkinson Agents
  • DNA, Complementary
  • Diphtheria Toxin
  • Hydroxydopamines
  • Levodopa