D1/D5 dopamine receptor stimulation increases striatal cholin ergic interneuron excitability in a mouse model of L DOPA induced dyskinesia

PAZ R; TUBERT, CECILIA; STAHL A; GIUGOVAZ TROPPER BARBARA; MURER MG; RELA, LORENA

Córdoba

Conferencia; XXXIII CONGRESO ANUAL SAN 2018; 2018

Sociedad Argentina de Investigacón en Neurociencias

Striatal cholinergic interneurons (SCIN) are important modulators of the striatal circuitrycontrolling go al directed behavior and voluntary movement. Enhanced striatal cholinergicsignaling 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 re ducingstriatal cholinergic activity may be beneficial for the treatment of LID. However, the mechanismsunderlying SCIN hyperactivity in the context of LID remain poorly understood. Here we aim toclarify how dopamine D1/D5 signaling modulates SCIN excita bility in PD and LID. We used sliceelectrophysiological recordings of mice fluorescently reporting SCIN to evaluate D1/D5 receptoragonism/antagonism on SCIN excitability in control and 6 OHDA lesioned mice with/without LDOPA treatment. Current clamp rec ordings revealed that L DOPA treatment exacerbates SCINhyperexcitability and alters their pattern of autonomous discharge. D1/D5 agonism markedlyincreases SCIN excitability in control and parkinsonian mice, whereas SCIN of dyskinetic animalsare already hyperexcitable and less sensitive to D1/D5 stimulation. Dopamine receptors modulatemultiple membrane currents that could explain this phenomenon. However, our preliminaryresults indicate that D1/D5 receptor stimulation decreases a KIR mediated potassium current inSCIN of control mice. These results point to novel molecular targets for potentially alleviating LID.