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Chemogenetic modulation of cholinergic interneurons reveals their regulating role on the direct and indirect output pathways from the striatum

Author:
  • Patrick Aldrin-Kirk
  • Andreas Heuer
  • Daniella Rylander Ottosson
  • Marcus Davidsson
  • Bengt Mattsson
  • Tomas Björklund
Publishing year: 2018-01
Language: English
Pages: 148-162
Publication/Series: Neurobiology of Disease
Volume: 109
Document type: Journal article
Publisher: Elsevier

Abstract english

The intricate balance between dopaminergic and cholinergic neurotransmission in the striatum has been thoroughly difficult to characterize. It was initially described as a seesaw with a competing function of dopamine versus acetylcholine. Recent technical advances however, have brought this view into question suggesting that the two systems work rather in concert with the cholinergic interneurons (ChIs) driving dopamine release. In this study, we have utilized two transgenic Cre-driver rat lines, a choline acetyl transferase ChAT-Cre transgenic rat and a novel double-transgenic tyrosine hydroxylase TH-Cre/ChAT-Cre rat to further elucidate the role of striatal ChIs in normal motor function and in Parkinson's disease. Here we show that selective and reversible activation of ChIs using chemogenetic (DREADD) receptors increases locomotor function in intact rats and potentiate the therapeutic effect of L-DOPA in the rats with lesions of the nigral dopamine system. However, the potentiation of the L-DOPA effect is accompanied by an aggravation of L-DOPA induced dyskinesias (LIDs). These LIDs appear to be driven primarily through the indirect striato-pallidal pathway since the same effect can be induced by the D2 agonist Quinpirole. Taken together, the results highlight the intricate regulation of balance between the two output pathways from the striatum orchestrated by the ChIs.

Keywords

  • Neurosciences
  • AAV
  • Animal models
  • Chemogenetics
  • Cholinergic interneurons
  • Direct pathway
  • DREADD
  • Indirect pathway
  • L-DOPA induced dyskinesias
  • Parkinson's disease
  • Transgenic rats

Other

Published
  • Molecular Neuromodulation
  • Developmental and Regenerative Neurobiology
  • ISSN: 0969-9961
Marcus Davidsson
E-mail: marcus [dot] davidsson [at] med [dot] lu [dot] se

Molecular Neuromodulation unit
Wallenberg Neuroscience Center
Department of Experimental Medical Science
BMC A10, 221 84 Lund, Sweden
 
Phone: +46 46 222 68 36
e-Mail: tomas [dot] bjorklund [at] med [dot] lu [dot] se