Translational Relevance of the Methylazoxymethanol Acetate Model in Schizophrenia: A Systematic Review of Behavioral and Neurobiological Findings.

Abstract

Schizophrenia is a neurodevelopmental psychiatric disorder whose circuit-level mechanisms remain incompletely understood. Among preclinical platforms, the methylazoxymethanol acetate (MAM) gestational model uniquely recapitulates the developmental, multidomain pathophysiology of schizophrenia, but the literature is fragmented, and prior systematic reviews have been limited to behavioral phenotypes. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 and CAMARADES (Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies) guidelines, we systematically searched PubMed, Embase, and Web of Science for original studies using the gestational MAM model in rats or mice. Findings were synthesized across 5 prespecified domains: behavioral, physiological, histological, genetic, and pharmacological. Of the 53 included studies, evidence converged on a single pathophysiological axis: gestational disruption of the ventral hippocampus (vHP) and medial prefrontal cortex produces parvalbumin interneuron loss, local excitatory/inhibitory imbalance, and vHP-nucleus accumbens-ventral tegmental area circuit hyperactivity, culminating in striatal dopamine excess. This axis maps bidirectionally to human postmortem, neuroimaging, and positron emission tomography evidence. Sex-stratified findings suggest that ovarian hormones modulate downstream circuit readout rather than the upstream cellular insult, accounting for attenuated behavioral phenotypes in female animals despite preserved cellular pathology. The MAM model recapitulates a convergent circuit-level pathophysiology of schizophrenia and is well positioned as a preclinical screening platform for next-generation non-D₂ therapeutics, including the muscarinic, TAAR1 (trace amine-associated receptor 1), and α5-GABA_AR (α5 subunit-containing gamma-aminobutyric acid type A receptor) approaches now entering clinical practice. Methodological harmonization, mixed-sex cohorts, and longitudinal designs will be critical to fully realize this translational potential.