Development of the MAM model of schizophrenia in mice: Sex similarities and differences of hippocampal and prefrontal cortical function

Schizophrenia is a debilitating disorder with complex and unclarified etiological factors. Sex differences have been observed in humans but animal models have only focused on male subjects. In this study, we report the establishment of the neurodevelopmental MAM model of schizophrenia in mice and compare the schizotypic-like characteristics and cognitive functions in both sexes. Pregnant mice were injected with methylazoxymethanol acetate (MAM) or saline on gestational day (GD) 16 (MAM-16) or 17 (MAM-17). Female MAM-16, but not MAM-17 treated mice exhibited enhanced hyperlocomotion after acute MK-801 administration, compared to saline treated mice. Male MAM-16, but not MAM-17, treated mice showed reduced pre-pulse inhibition of the acoustic startle reflex. Both male and female MAM-16 and MAM-17 treated mice exhibited smaller hippocampal (HPC) size and thinning of the prefrontal cortex (PFC), but only male MAM-16 treated mice showed decreased parvalbumin expression in HPC and PFC. Similarly, both male and female MAM-16 treated mice displayed impaired contextual fear memory and significantly reduced long-term potentiation (LTP) in the HPC CA1 synapses. However, male, but not female, MAM-16 treated mice exhibited deficits in the delayed alternation task and LTP in layer II PFC synapses. Proteomic analyses of PFC lysates further showed significant MAM- and sex-dependent differences in protein expression regulation. Our results demonstrate that while both male and female mice, prenatally exposed to MAM on GD16, display several core schizophrenia-like deficits and impairments in the hippocampus, only male MAM-treated mice have PFCdependent cognitive deficits.