L-DOPA causes oscillatory activity in striatal cholinergic interneurons from parkinsonian mice via dopamine D1/D5 receptors

PAZ, RODRIGO MANUEL; AMARILLO, YIMY; TUBERT, CECILIA; RELA, LORENA; STAHL, AGOSTINA MONICA; MURER, MARIO GUSTAVO

Virtual

Congreso; XXXV Congreso Anual; 2020

Sociedad Argentina de Investigación en Neurociencias

Striatal cholinergic interneurons (SCIN) are key modulators of the striatal circuitry controlling voluntary movement and goal-directed behavior. Aberrant striatal cholinergic signalling contributes to the symptoms of Parkinson?s disease (PD) and L-dopa induced dyskinesia (LID), a major complication of antiparkinsonian L-dopa therapy. However, the mechanisms causing SCIN dysfunction in PD and LID remain uncertain. Here we used slice electrophysiological approaches to show that SCIN exhibit enhanced Kir and reduced leak currents in a mouse model of LID. These changes cause exacerbated hyperpolarizing responses that coexist with an enhanced excitability, resulting in a burst-pause firing pattern that persists after the dyskinetic effect of an L-dopa dose has worn off. Additionally, we show that a negative slope region of the Kir conductance curve is responsible for the oscillatory behaviour. Stimulation of dopamine D1/D5 receptors mimics the physiological changes induced by L-dopa administration, but D1/D5 receptor blockade does not modify the persistent hyperexcitability and oscillatory activity observed in dyskinetic mice. However, blunting intracellular cAMP signaling restores normal hyperpolarizing responses and dampens oscillatory activity in dyskinetic mice. Our data unravel a mechanism causing aberrant SCIN activity in LID and point at D1/D5 receptor regulation of Kir2 and leak channels as potential targets to restore normal striatal cholinergic function in PD and LID.