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

Aldrin-Kirk, Patrick LU ; Heuer, Andreas LU ; Rylander Ottosson, Daniella; Davidsson, Marcus LU ; Mattsson, Bengt LU and Björklund, Tomas LU (2017) In Neurobiology of Disease
Abstract

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... (More)

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.

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organization
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Contribution to journal
publication status
epub
subject
keywords
AAV, Animal models, Chemogenetics, Cholinergic interneurons, Direct pathway, DREADD, Indirect pathway, L-DOPA induced dyskinesias, Parkinson's disease, Transgenic rats
in
Neurobiology of Disease
pages
15 pages
publisher
Elsevier
external identifiers
  • scopus:85032212631
ISSN
0969-9961
DOI
10.1016/j.nbd.2017.10.010
language
English
LU publication?
yes
id
58bdbf8b-cb0c-4890-80c3-1b810f44ac8c
date added to LUP
2017-11-07 09:58:05
date last changed
2018-01-07 12:24:58
@article{58bdbf8b-cb0c-4890-80c3-1b810f44ac8c,
  abstract     = {<p>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.</p>},
  author       = {Aldrin-Kirk, Patrick and Heuer, Andreas and Rylander Ottosson, Daniella and Davidsson, Marcus and Mattsson, Bengt and Björklund, Tomas},
  issn         = {0969-9961},
  keyword      = {AAV,Animal models,Chemogenetics,Cholinergic interneurons,Direct pathway,DREADD,Indirect pathway,L-DOPA induced dyskinesias,Parkinson's disease,Transgenic rats},
  language     = {eng},
  month        = {10},
  pages        = {15},
  publisher    = {Elsevier},
  series       = {Neurobiology of Disease},
  title        = {Chemogenetic modulation of cholinergic interneurons reveals their regulating role on the direct and indirect output pathways from the striatum},
  url          = {http://dx.doi.org/10.1016/j.nbd.2017.10.010},
  year         = {2017},
}