D1/D5 dopamine receptor stimulation increases striatal cholinergic interneuron excitability in L-DOPA-induced dyskinesia

CECILIA TUBERT; GUSTAVO MURER; AGOSTINA STAHL; LORENA RELA; RODRIGO MANUEL PAZ; BÁRBARA GIUGOVAZ TROPPER

Córdoba

Congreso; XXXIII Congreso Anual. Sociedad Argentina de Investigación en Neurociencias; 2018

Sociedad Argentina de Investigación en Neurociencias

Striatal cholinergic interneurons (SCIN) are important modulators of the striatal circuitry controlling goal directed behavior and voluntary movement. Enhanced striatal cholinergic signaling has been related to the genesis of movement disorders such as Parkinson´s disease (PD) and L-DOPA-induced dyskinesia (LID). Indeed, recent studies provide evidence that reducing striatal cholinergic activity may be beneficial for the treatment of LID. However, the mechanisms underlying SCIN hyperactivity in the context of LID remain poorly understood. Here we aim to clarify how dopamine D1/D5 signaling modulates SCIN excitability in PD and LID. We used slice electrophysiological recordings of mice fluorescently reporting SCIN to evaluate D1/D5 receptor agonism/antagonism on SCIN excitability in control and 6-OHDA lesioned mice with/without LDOPA treatment. Current clamp recordings revealed that L-DOPA treatment exacerbates SCIN hyperexcitability and alters their pattern of autonomous discharge. D1/D5 agonism markedly increases SCIN excitability in control and parkinsonian mice, whereas SCIN of dyskinetic animals are already hyperexcitable and less sensitive to D1/D5 stimulation. Dopamine receptors modulate multiple membrane currents that could explain this phenomenon. However, our preliminary results indicate that D1/D5 receptor stimulation decreases a KIR-mediated potassium current in SCIN of control mice. These results point to novel molecular targets for potentially alleviating LID.