Striatal Cholinergic Interneuron Dysfunction in Parkinson’s Disease & its Therapy | NYU Langone Health

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Kang Lab Research Striatal Cholinergic Interneuron Dysfunction in Parkinson’s Disease & its Therapy

Striatal Cholinergic Interneuron Dysfunction in Parkinson’s Disease & its Therapy

Chronic Parkinson’s disease (PD) therapy often produces levodopa-induced dyskinesia (LID). These involuntary abnormal movements can become debilitating and can limit the efficacy of levodopa. We are searching for differential molecular and circuitry mechanisms of beneficial therapeutic response versus aberrant responses such as LID. While many factors contribute to LID, we previously showed that the striatal cholinergic interneurons (ChIs) are activated and anticholinergics or killing ChIs reduce LID.

Immunostaining of pERK-expressing cells (green) and cholinergic neurons (cholineacetyl transferase; red) show shift of pERK expression from spiny projection neurons (acute) to cholinergic interneurons after chronic levodopa treatment (7 weeks) in mice that develop levodopa-induced dyskinesia. (Ding Y … Kang UJ. Enhanced striatal cholinergic neuronal activity mediates L-DOPA-induced dyskinesia in parkinsonian mice. PNAS. 2011. DOI.
3D reconstruction of striatal cholinergic neurons filled with biocytin after electrophysiological recording in slice preparation.

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. These findings suggest that targeting ChIs with channel-specific modulators may provide therapeutic approaches for alleviating L-DOPA-induced dyskinesia in PD patients. (Choi et al. Alterations in the intrinsic properties of striatal cholinergic interneurons after dopamine lesion and chronic L-DOPA. eLife. 2020. DOI.)

We are currently investigating how direct modulation of ChI activity with chemogenetic and optogenetic techniques influences LID.