The striatal hypercholinergic condition in Parkinson’s disease (PD) and levodopa-induced dyskinesia are both caused by increased striatal cholinergic interneuron activity. Dyskinesia and motor fluctuations become severely burdensome in severe PD, and treatment options are limited. Targeting cholinergic interneurons is a possible treatment approach because systemic injection of anticholinergics can increase extrastriatal-related symptoms. As a result, figuring out what causes aberrant cholinergic interneuron activity in severe PD with motor fluctuations and dyskinesia might lead to novel molecular treatment targets.
The inherent changes of cholinergic interneurons in the 6-hydroxydopamine mouse model of PD treated with levodopa were investigated using ex vivo electrophysiological recordings coupled with pharmacological and morphological research. In the Parkinsonian “off levodopa” state, cholinergic interneurons show pathological burst-pause activity. This is regulated by a cyclic adenosine monophosphate (cAMP) pathway that has a sustained ligand-independent activity of dopamine D1/D5 receptor signaling. Burst pause activity is caused by a dysregulation of membrane ion channels that leads to enhanced inward-rectifier potassium type 2 (Kir2) and decreased leak currents, which can be reduced by pharmacological suppression of intracellular cAMP. Persistent cholinergic interneuron burst-pause firing can be induced by a single challenge with a dyskinetogenic dosage of levodopa.
The findings revealed a mechanism that causes abnormal cholinergic interneuron burst-pause activity in levodopa-treated Parkinsonian mice. By restoring normal cholinergic interneuron activity, targeting D5-cAMP signaling, and the control of Kir2 and leak channels, parkinsonism and dyskinesia may be alleviated.