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

## TL;DR

This study shows that DARPP-32, a protein in brain cells, plays a key role in regulating sleep and could help treat sleep issues in Parkinson’s disease.

## Contribution

DARPP-32 is identified as a novel, cell-specific regulator of sleep and a potential therapeutic target for Parkinson’s-related excessive daytime sleepiness.

## Key findings

- DARPP-32 deletion in D2R/A2AR-expressing neurons reduces NREM sleep and counteracts excessive daytime sleepiness in Parkinsonism.
- DARPP-32 loss in D1R neurons increases NREM sleep stability during the inactive phase.
- Sleep fragmentation in Parkinsonism is not improved by DARPP-32 deletion in D1R neurons.

## Abstract

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.

•D1R- and A2AR/D2R-expressing neurons regulate NREM sleep via the modulation of DARPP-32•Loss of DARPP-32 in D1R neurons increases NREM sleep stability•Loss of DARPP-32 in A2AR/D2R neurons decreases NREM sleep•DARPP-32 deletion in A2AR/D2R neurons counteracts EDS in experimental PD

D1R- and A2AR/D2R-expressing neurons regulate NREM sleep via the modulation of DARPP-32

Loss of DARPP-32 in D1R neurons increases NREM sleep stability

Loss of DARPP-32 in A2AR/D2R neurons decreases NREM sleep

DARPP-32 deletion in A2AR/D2R neurons counteracts EDS in experimental PD

Neuroscience; Behavioral neuroscience; Cognitive neuroscience