Chemogenetic modulation of cholinergic interneurons reveals their regulating role on the direct and indirect output pathways from the striatum
(2018) In Neurobiology of Disease 109. p.148-162- 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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- author
- Aldrin-Kirk, Patrick LU ; Heuer, Andreas LU ; Ottosson, Daniella LU ; Davidsson, Marcus LU ; Mattsson, Bengt LU and Björklund, Tomas LU
- organization
-
- Human Neural Developmental Biology (research group)
- Behavioural Neuroscience Laboratory (research group)
- Regenerative Neurophysiology (research group)
- Molecular Neuromodulation (research group)
- MultiPark: Multidisciplinary research focused on Parkinson´s disease
- StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
- Developmental and Regenerative Neurobiology (research group)
- publishing date
- 2018-01
- type
- Contribution to journal
- publication status
- published
- 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
- volume
- 109
- article number
- 109
- pages
- 148 - 162
- publisher
- Elsevier
- external identifiers
-
- scopus:85032212631
- pmid:29037828
- 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
- 2024-09-16 11:50:39
@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 Ottosson, Daniella and Davidsson, Marcus and Mattsson, Bengt and Björklund, Tomas}}, issn = {{0969-9961}}, keywords = {{AAV; Animal models; Chemogenetics; Cholinergic interneurons; Direct pathway; DREADD; Indirect pathway; L-DOPA induced dyskinesias; Parkinson's disease; Transgenic rats}}, language = {{eng}}, pages = {{148--162}}, 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}}, doi = {{10.1016/j.nbd.2017.10.010}}, volume = {{109}}, year = {{2018}}, }