Acetylation of Histones in the Nucleus Accumbens Increases the Expression of Dopamine Transporters to Regulate Executive Function in Sapap3 Knockout Mice

Obsessive‐compulsive disorder (OCD) is a chronic and debilitating psychiatric condition characterized by persistent, intrusive thoughts (obsessions) and repetitive ritualistic behaviors (compulsions). Accumulating evidence suggests that individuals with OCD demonstrate marked cognitive impairments, especially in executive function domains, including cognitive flexibility and working memory. Although existing therapeutic approaches (e.g., serotonin reuptake inhibitors and cognitive‐behavioral therapy) can partially mitigate behavioral symptoms, their effectiveness in improving cognitive impairments remains limited. Although dopaminergic dysregulation has been implicated in OCD, the involvement of dopamine transporter (DAT) polymorphisms in cognitive flexibility and working memory impairments remains unclear, limiting the development of targeted therapeutic interventions. Although current investigations predominantly focus on dopamine (DA) D1/D2 receptors and serotonin transporters, the contribution of the DAT to OCD pathophysiology remains insufficiently explored. In the present study, we utilized Sapap3 knockout (KO) mice as a preclinical OCD model to examine dopaminergic dysregulation. Using ELISA, we conducted systematic comparisons of both dopaminergic levels and DAT expression between Sapap3 KO and wild‐type (WT) mice. Additionally, we implemented targeted epigenetic modulation via histone acetylation in the nucleus accumbens (NAc) of Sapap3 KO mice. Our data demonstrated a significant decrease in DAT expression in the NAc of Sapap3 KO mice compared to WT ( p = 0.0019). Strikingly, the administration of the histone deacetylase inhibitor 4‐phenylbutyric acid (PBA) normalized DAT expression in KO mice to levels statistically equivalent to WT mice ( p = 0.1107), achieving complete functional recovery of DAT deficiency. This restoration of DAT expression ( p = 0.1107 PBA vs. WT) was accompanied by a significant reduction in the abnormally elevated baseline DA levels in Sapap3 KO mice (pretreatment: 192.46 ± 6.69 pg/mg; posttreatment: 173.67 ± 4.10 pg/mg, p < 0.01), which consequently improved executive function impairments. Our findings demonstrate that DAT polymorphisms represent a previously unrecognized pathogenic factor in cognitive impairment associated with OCD. Investigations of histone acetylation regulatory mechanisms revealed that changes in histone acetylation levels directly regulate DAT expression. We provide mechanistic evidence showing that epigenetic regulation of DAT expression can effectively reverse these neurological deficits, particularly through modulation of histone acetylation status to significantly improve DAT functional abnormalities, thereby identifying a novel and promising therapeutic target for OCD treatment.