Sex-dependent behavioral and neuronal alterations in the F2 generation of a neurodevelopmental mouse model for schizophrenia

Abstract

Schizophrenia is a complex neurodevelopmental disorder influenced by genetic and environmental factors. Using a maternal methylazoxymethanol acetate (MAM) exposure model, we investigated behavioral, neuronal, and glial alterations in the F2 generation to explore the intergenerational effects of prenatal neurodevelopmental disruption. Our study demonstrates that prenatal MAM exposure induces the transgenerational transmission of schizophrenia-like phenotypes in F2 offspring. Both male and female F2 mice exhibited deficits in sensorimotor gating and recognition memory impairments, reflecting core cognitive dysfunctions commonly observed in schizophrenia. Notably, male-specific phenotypes emerged in the form of risk-avoidance deficits, accompanied by significant reductions in NeuN-positive mature neurons and parvalbumin-positive interneurons in the CA1 region of the hippocampus. In contrast, dentate gyrus neurogenesis was impaired in both sexes, while glial cells (microglia and astrocytes) remained unaffected, indicating a neuron-specific vulnerability to intergenerational disruptions. These findings highlight sex-dependent neuronal and behavioral consequences in the offspring of a schizophrenia mouse model, providing insights into intergenerational neurodevelopmental disruptions and their potential contributions to schizophrenia-like phenotypes.