Mechanisms of striatal cholinergic interneuron hyperexcitability in animal models of Parkinson's disease and L-DOPA-induced dyskinesia

MARIO GUSTAVO MURER; RODRIGO M PAZ; LORENA RELA; CECILIA TUBERT

Buenos Aires

Congreso; 2nd FALAN Congress; 2016

Federation of Latin American and Caribbean Neuroscience Societies

Parkinson disease (PD) is a neurodegenerative disorder caused by loss of dopaminergic innervation of the striatum, where an imbalance between dopamine (DA) and acetylcholine (ACh) levels emerges. Cholinergic interneurons (ChIs) are the main source of striatal ACh and become hyperactive in PD and L-DOPA-induced dyskinesia (LID) animal models. Recent studies support a contribution of ChI dysfunction to PD symptoms and LID, but mechanisms underlying ChI hyperactivity in these conditions remain poorly understood This project aims to clarify how dopamine signaling modulates ChI activity and to identify mechanisms governing ChI hyperexcitability in experimental parkinsonism and LID. We use slice electrophysiological recordings of mice fluorescently reporting ChIs to evaluate dopamine receptor agonism/antagonism on ChI excitability in control and 6-OHDA lesioned mice with/without L-DOPA treatment. We focus on dopaminergic modulation of Kv1 channels previously identified as mediators of ChI hyperexcitability in a mouse model of PD. A common view is that D2-dopamine receptor activation decreases ChI activity and ACh release, and that reduced D2-receptor activation might underlie increased ACh release in Parkinsonism. Nevertheless, our preliminary results show that activation of D2-receptors with quinpirole markedly increases the membrane excitability of ChIs in control mice, suggesting a mechanism through which L-DOPA therapy can increase (rather than decrease) ChI activity in LID.