Poly ADP-ribosylation regulates Arc expression and promotes adaptive stress-coping.

Rationale: Rapid adaptation to stressful events is essential for survival and requires acute stress response and stress-coping strategy. However, the molecular mechanisms that govern this coping strategy have yet to be fully discovered.

Objectives: This study aims to investigate the effects of poly ADP-ribosylation (PARylation) on stress-coping strategies following acute stress and to identify the target genes influenced by Parp1-induced histone PARylation.

Methods: Mice were subjected to a forced swim test, a well-established acute stress paradigm, to evaluate cortical PARylation and assess the expression of activity-dependent genes. The pharmacological inhibition of Parp1 was conducted using ABT888 (Veliparib) to determine its effects on stress-coping behavior and related molecular changes.

Results: The forced swim test increased cortical PARylation and upregulated the expression of activity-dependent genes. Systemic inhibition of Parp1 with ABT888 led to impaired stress-coping behavior, evidenced by a reduced immobility response during a subsequent forced swim test done 24 hours later. This impairment was associated with decreased chromatin PARylation and histone H4 acetylation at the Arc promoter and reduced Arc expression observed one hour after Parp1 inhibition.

Conclusion: Our findings indicate that chromatin PARylation at the Arc promoters regulates histone H4 acetylation and Arc gene expression, and a subsequent impact on successful stress-coping behavior in response to acute stress.