Abnormalities in behavior relevant to schizophrenia in embryonic day 17 MAM-exposed rodent models: A systematic review and meta-analysis

Background

Neurodevelopmental disorders, notably schizophrenia, present ongoing challenges in mental health. Methylazoxymethanol (MAM), a potent neurodevelopmental disruptor, is implicated in inducing schizophrenia-like structural and functional alterations in rodent models. This study conducts a systematic review and meta-analysis to assess comprehensively the behavioral consequences of embryonic MAM exposure in rodents, focusing on diverse paradigms reflective of schizophrenia-related phenotypes.

Methods

Employing a meticulous search strategy across PubMed, Embase, Cochrane Library, Sino Med, CNKI, Weip Database, Wan Fang, and Web of Science, this study adheres to PRISMA guidelines. The analysis includes studies examining the impact of embryonic MAM exposure on behavioral outcomes, such as Prepulse Inhibition (PPI), social interaction (SI), novel object recognition (NOR), elevated plus maze (EPM) performance, and open field test (OFT) results. The study protocol is registered with PROSPERO, number 42024521442 CRD.

Results

Involving 19 studies, the meta-analysis reveals nuanced behavioral alterations. MAM-exposed male rats in the EPM group exhibit a Mean Difference of −0.27 (95 % CI: [−1.02, 0.49]) during puberty, with a broader Mean Difference of −0.50 (95 % CI: [−1.97, 0.96]) in adulthood. Combining both stages yields an overall Mean Difference of −0.31 (95 % CI: [−1.01, 0.38]), indicating potential EPM performance differences. Subgroup analysis by MAM dosage levels reveals a Mean Difference of −0.90 (95 % CI: [−1.86, 0.05]) for moderate-dose MAM and 0.65 (95 % CI: [0.29, 1.02]) for high-dose MAM. In the OFT group, adulthood shows a Mean Difference of −1.22 (95 % CI: [−2.14, −0.29]), emphasizing altered exploratory behavior. The NOR group indicates significant Mean Differences of −6.18 (95 % CI: [−8.41, −3.94]) in adulthood, signifying recognition memory deficits. SI assessments show consistent negative Mean Differences during puberty and adulthood for male rats (−1.88 and − 1.87, respectively) and female rats in preestrus and estrus (−1.09).

Conclusions

This systematic review and meta-analysis offer a comprehensive overview of behavioral consequences linked to embryonic MAM exposure in rodents. Findings underscore intricate relationships between MAM and various behavioral domains relevant to schizophrenia. Dose-dependent effects, developmental stage considerations, and potential sex-specific influences contribute to the complexity of MAM-induced alterations, advancing our understanding of neurodevelopmental disruptions and suggesting avenues for future research and therapeutic interventions targeting the developmental origins of psychiatric disorders.