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

Another part of the motor response complications in chronic Parkinson’s disease (PD) therapy often manifest as 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 severity of LID is reduced by selectively killing striatal cholinergic interneurons (ChIs), indicating their prominent and presumably selective contribution to LIDs.

We are currently investigating how ChIs contribute to LID by assessing how their physiology changes in response to dopamine loss and levodopa treatment using slice and in vivo electrophysiology, ChI-selective RNA profiling, and direct modulation of ChI activity with chemogenetic and optogenetic techniques.

3D reconstruction of striatal cholinergic neurons filled with biocytin after electrophysiological recording in slice preparation.
Immunostaining of pERK-expressing cells and cholinergic neurons (cholineacetyl transferase) 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.

Note: In the image above, immunostaining of pERK-expressing cells is shown in green and immunostaining of cholinergic neurons (cholineacetyl transferase) is marked in red. (Ding Y … Kang UJ. Enhanced striatal cholinergic neuronal activity mediates L-DOPA-induced dyskinesia in parkinsonian mice. PNAS. 2011. DOI.)