Dataset Information

Alterations in the intrinsic properties of striatal cholinergic interneurons after dopamine lesion and chronic L-DOPA.

ABSTRACT: Changes in striatal cholinergic interneuron (ChI) activity are thought to contribute to Parkinson's disease pathophysiology and dyskinesia from chronic L-3,4-dihydroxyphenylalanine (L-DOPA) treatment, but the physiological basis of these changes is unknown. We find that dopamine lesion decreases the spontaneous firing rate of ChIs, whereas chronic treatment with L-DOPA of lesioned mice increases baseline ChI firing rates to levels beyond normal activity. The effect of dopamine loss on ChIs was due to decreased currents of both hyperpolarization-activated cyclic nucleotide-gated (HCN) and small conductance calcium-activated potassium (SK) channels. L-DOPA reinstatement of dopamine normalized HCN activity, but SK current remained depressed. Pharmacological blockade of HCN and SK activities mimicked changes in firing, confirming that these channels are responsible for the molecular adaptation of ChIs to dopamine loss and chronic L-DOPA treatment. These findings suggest that targeting ChIs with channel-specific modulators may provide therapeutic approaches for alleviating L-DOPA-induced dyskinesia in PD patients.

SUBMITTER: Choi SJ

PROVIDER: S-EPMC7380940 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Alterations in the intrinsic properties of striatal cholinergic interneurons after dopamine lesion and chronic L-DOPA.

Choi Se Joon SJ Ma Thong C TC Ding Yunmin Y Cheung Timothy T Joshi Neal N Sulzer David D Mosharov Eugene V EV Kang Un Jung UJ

eLife 20200720

Changes in striatal cholinergic interneuron (ChI) activity are thought to contribute to Parkinson's disease pathophysiology and dyskinesia from chronic L-3,4-dihydroxyphenylalanine (L-DOPA) treatment, but the physiological basis of these changes is unknown. We find that dopamine lesion decreases the spontaneous firing rate of ChIs, whereas chronic treatment with L-DOPA of lesioned mice increases baseline ChI firing rates to levels beyond normal activity. The effect of dopamine loss on ChIs was d ...[more]

PMID: 32687053

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Project description:Striatal cholinergic dysfunction is a common phenotype associated with various forms of dystonia in which anti-cholinergic drugs have some therapeutic benefits. However, the underlying substrate of striatal cholinergic defects in dystonia remain poorly understood. In this study, we used a recently developed knock-in mouse model of dopamine-responsive dystonia (DRD) with strong symptomatic responses to anti-cholinergic drugs, to assess changes in the prevalence and morphology of striatal cholinergic interneurons (ChIs) in a model of generalized dystonia. Unbiased stereological neuronal counts and Sholl analysis were used to address these issues. To determine the potential effect of aging on the number of ChIs, both young (3 months old) and aged (15 months old) mice were used. For purpose of comparisons with ChIs, the number of GABAergic parvalbumin (PV)-immunoreactive striatal interneurons was also quantified in young mice. Overall, no significant change in the prevalence of ChIs and PV-immunoreactive cells was found throughout various functional regions of the striatum in young DRD mice. Similar results were found for ChIs in aged animals. Subtle changes in the extent and complexity of the dendritic tree of ChIs were found in middle and caudal regions of the striatum in DRD mice. Additional immunohistochemical data also suggested lack of significant change in the expression of striatal cholinergic M1 and M4 muscarinic receptors immunoreactivity in DRD mice. Thus, together with our previous data from a knock-in mouse model of DYT-1 dystonia (Song et al., 2013), our data further suggest that the dysregulation of striatal cholinergic transmission in dystonia is not associated with major neuroplastic changes in the morphology or prevalence of striatal ChIs. Highlights -There is no significant change in the number of striatal ChIs in young and aged mice model of DRD-There is no significant change in the prevalence of striatal GABAergic PV-containing interneurons in the striatum of young mice models of DRD-Subtle morphological changes in the dendritic arborization of striatal ChIs are found in the middle and caudal tiers of the striatum in young mice models of DRD-The levels of both M1 and M4 muscarinic receptors immunoreactivity are not significantly changed in the striatum of DRD mice-Major changes in the prevalence and morphology of striatal ChIs are unlikely to underlie striatal cholinergic dysfunction in DRD.

Dataset Information

Alterations in the intrinsic properties of striatal cholinergic interneurons after dopamine lesion and chronic L-DOPA.

Publications

Alterations in the intrinsic properties of striatal cholinergic interneurons after dopamine lesion and chronic L-DOPA.

Similar Datasets

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