IDENTIFICATION OF DARPP-32 AS A NOVEL SLEEP REGULATOR IN PHYSIOLOGICAL CONDITIONS AND EXPERIMENTAL PARKINSONISM

Excessive daytime sleepiness (EDS) and sleep fragmentation are prevalent non-motor symptoms of Parkinson’s disease (PD) that substantially impair quality of life. Despite their clinical relevance, effective treatments remain limited, reflecting an incomplete understanding of the underlying mechanisms. Dopamine- and adenosine-dependent signaling in the striatum has emerged as a key regulator of sleep–wake control. DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of 32 kDa) is a major intracellular integrator of these neuromodulatory pathways, yet its role in sleep regulation remains unexplored.
Here, we investigated the cell-type-specific contribution of DARPP-32 in dopamine D1 receptor (D1R)- and adenosine A2A receptor (A2AR)-expressing neurons. Using targeted genetic depletion combined with EEG/EMG recordings, we demonstrate that DARPP-32 exerts distinct effects on NREM sleep across striatal neuronal populations. Loss of DARPP-32 in A2AR neurons selectively reduced NREM sleep during the active phase of the sleep–wake cycle, whereas its loss in D1R neurons enhanced NREM sleep stability during the inactive phase.
Importantly, in a 6-hydroxydopamine mouse model of PD, selective deletion of DARPP-32 in A2AR neurons mitigated sleepiness during the active period, effectively protecting against EDS. Consistent with this mechanism, administration of the selective A2AR antagonist istradefylline—recently shown to ameliorate sleep disturbances in PD patients—also reduced EDS in the mouse PD model.
Together, these findings identify DARPP-32-mediated signaling in A2AR neurons as a critical regulator of NREM sleep and provide a mechanistic basis for targeting this pathway to alleviate sleep disturbances in PD.