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

• Published in: Neurobiology of disease 2018-01, Vol.109 (Pt A), p.148-162
• Main Authors: Aldrin-Kirk, Patrick, Heuer, Andreas, Rylander Ottosson, Daniella, Davidsson, Marcus, Mattsson, Bengt, Björklund, Tomas
• Format: Article
• Language: English
• Subjects: AAV; Animal models; Animals; Basic Medicine; Chemogenetics; Choline O-Acetyltransferase - genetics; Cholinergic interneurons; Cholinergic Neurons - cytology; Cholinergic Neurons - metabolism; Cholinergic Neurons - physiology; Corpus Striatum - cytology; Corpus Striatum - metabolism; Corpus Striatum - physiology; Direct pathway; Dopamine - metabolism; Dopaminergic Neurons - cytology; Dopaminergic Neurons - metabolism; Dopaminergic Neurons - physiology; DREADD; Dyskinesia, Drug-Induced - metabolism; Dyskinesia, Drug-Induced - physiopathology; Female; Indirect pathway; Interneurons - cytology; Interneurons - metabolism; Interneurons - physiology; L-DOPA induced dyskinesias; Levodopa - administration & dosage; Locomotion; Male; Medical and Health Sciences; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; Neurosciences; Neurovetenskaper; Parkinson Disease - metabolism; Parkinson Disease - physiopathology; Parkinson's disease; Rats, Long-Evans; Rats, Sprague-Dawley; Rats, Transgenic; Receptors, Dopamine D1 - agonists; Receptors, Dopamine D1 - physiology; Receptors, Dopamine D2 - agonists; Receptors, Dopamine D2 - physiology; Transgenic rats; Tyrosine 3-Monooxygenase - genetics
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2017.10.010

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. •Activation of striatal cholinergic interneurons increases motor function in rats.•Cholinergic interneurons potentiate the effect of L-DOPA in Parkinsonian rats.•L-DOPA induced dyskinesias are aggravated by the cholinergic interneurons.•The potentiation of LIDs is driven through the indirect striatal output pathway.