<p>Aripiprazole has become one of the most commonly prescribed antipsychotics, including in pregnant women, owing to a broad range of indications for psychiatric disorders and relatively few metabolic side effects. Compared with that of other antipsychotics, data regarding the safety of gestational aripiprazole exposure for offspring neurodevelopment are limited. This study investigated how prenatal exposure to aripiprazole affects the hippocampal neuroplasticity of adult offspring and whether any such effect can be reversed by environmental enrichment. Aripiprazole was administered to pregnant C57BL/6 N mice from embryonic days 6–16. Key findings revealed that aripiprazole exposure (3.0 mg/kg) persistently impaired hippocampal plasticity and related cognitive function in adult male offspring, including reduced adult neurogenesis, dendrite retraction and spine loss of granule cells in the dentate gyrus and recognition memory deficits. The proteomics results revealed decreased hippocampal levels of dopamine and cAMP-regulated phosphoprotein 32 kDa (DARPP-32), a key regulatory molecule of dopamine signaling. In addition, lower concentrations of dopamine and higher concentrations of serotonin in the hippocampus were detected in aripiprazole-exposed mice via HPLC with electrochemical detection. Notably, environmental enrichment reversed the disruption of spatial memory function and partially improved impaired hippocampal neuronal plasticity in prenatally aripiprazole-exposed mouse offspring. Our results provide insight into the long-term negative effects of early-life exposure to aripiprazole on hippocampal plasticity and behavior, which may be related to disturbances in the dopamine and serotonin transmitter systems. As a relatively “natural” intervention, environmental enrichment has potential for future clinical application.</p><p></p>