ENVIRONMENTAL ENRICHMENT IMPROVES THE DEFICITS OF HIPPOCAMPAL NEUROPLASTICITY AND COGNITION IN PRENATALLY ARIPIPRAZOLE EXPOSED MICE OFFSPRING

Abstract Background Aripiprazole has become one of the most commonly prescribed antipsychotics, including in pregnant women due to a broad range of indications in psychiatric disorders and relatively fewer metabolic side effects (1-2). Compared with other antipsychotics, data regarding the safety of gestational aripiprazole exposure on offspring neurodevelopment is fewer (3). Aims & Objectives This study investigates how prenatal aripiprazole exposure affects hippocampal neuroplasticity of adult mice offspring and if any such effect can be reversed by environmental enrichment. Methods Aripiprazole was administered to pregnant C57BL/6N mice from embryonic day 6 to 16. Behavioral tests, immunohistochemical staining, high performance liquid chromatography electrochemical detector (HPLC-ECD), Golgi-Cox technique, LC-MS/MS analysis, and real-time quantitative reverse transcription PCR were used to determine the effects of prenatal antipsychotic exposure on the plasticity of the hippocampus and related behavior in adult male mice. The intervention effects of an enriched environment on the negative neurodevelopmental outcomes (4) in offspring induced by exposure to aripiprazole during pregnancy were evaluated. Results Main findings show aripiprazole exposure persistently impaired hippocampal plasticity and related cognitive function of adult mice offspring, including decreased adult neurogenesis, dendrite retraction and spine loss of granule cells in the dentate gyrus, and recognition memory deficits. The proteomics results revealed that decreased hippocampal expression of DARPP-32, a key regulatory molecule of dopamine signaling (5). In addition, lower concentrations of dopamine and higher concentrations of serotonin in the hippocampus were found in aripiprazole-exposed mice measured by HPLC with electrochemical detection. Notably, environmental enrichment reversed the disruption of spatial memory function and partially improved the impaired hippocampal neuronal plasticity in prenatally aripiprazole-exposed mice offspring. Discussion & Conclusion 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 the disturbance of dopamine and serotonin transmitter systems. Environmental enrichment as a relatively "natural" intervention has the potential for future clinical application. References 1.Reutfors J, Cesta C E, Cohen J M, et al. Antipsychotic drug use in pregnancy: A multinational study from ten countries[J]. Schizophr Res, 2020,220:106-115. 2.Poels E, Schrijver L, Kamperman A M, et al. Long-term neurodevelopmental consequences of intrauterine exposure to lithium and antipsychotics: a systematic review and meta-analysis[J]. Eur Child Adolesc Psychiatry, 2018,27(9):1209-1230. 3.Straub L, Hernandez-Diaz S, Bateman B T, et al. 3.Association of Antipsychotic Drug Exposure in Pregnancy With Risk of Neurodevelopmental Disorders: A National Birth Cohort Study[J]. JAMA Intern Med, 2022,182(5):522-533. 4.Forbes T A, Goldstein E Z, Dupree J L, et al. Environmental enrichment ameliorates perinatal brain injury and promotes functional white matter recovery[J]. Nat Commun, 2020,11(1):964. 5.Nishi A, Shuto T. Potential for targeting dopamine/DARPP-32 signaling in neuropsychiatric and neurodegenerative disorders[J]. Expert Opin Ther Targets, 2017,21(3):259-272.