Identification of DARPP-32 as a novel sleep regulator in physiological conditions and experimental Parkinsonism

Sleep disorders are common in Parkinson's disease (PD) and respond poorly to current pharmacological treatments, partly due to limited understanding of their underlying mechanisms. Using polysomnographic recordings, we investigated the role of dopamine- and cAMP-regulated phosphoprotein 32 kDa (DARPP-32) in sleep-wake regulation and PD-related sleep dysfunction. In naive mice, the selective ablation of DARPP-32 in striatal projection neurons (SPN) co-expressing dopamine D2 and adenosine A2A receptors reduced NREM sleep during the active phase of the circadian cycle, whereas its deletion in dopamine D1 receptor-expressing SPN increased NREM sleep stability during the inactive phase. In a mouse model of PD, excessive daytime sleepiness (EDS), a common non-motor symptom in PD, was abolished by DARPP-32 deletion in D2R/A2AR-expressing SPN but not in D1R-expressing SPN, which also failed to improve sleep fragmentation. Together, these findings identify DARPP-32 as a key regulator of sleep-wake function and a cell-specific target for alleviating PD-related EDS.