Prenatal exposure to MAM impairs mPFC and hippocampal inhibitory function in mice during adolescence and adulthood

Abstract

Neurodevelopmental abnormalities are considered to be one of the important causes of schizophrenia. The offspring of methylazoxymethanol acetate (MAM)-exposed mice are recognized for the dysregulation of neurodevelopment and well-characterized with schizophrenia-like phenotypes. However, the inhibition-related properties of the medial prefrontal cortex (mPFC) and hippocampus throughout adolescence and adulthood have not been systematically elucidated. In this study, both 10 mg/kg and 15 mg/kg MAM-exposed mice exhibited schizophrenia-related phenotypes in both adolescence and adulthood, including spontaneous locomotion hyperactivity and deficits in prepulse inhibition (PPI). We observed that there was an obvious parvalbumin (PV) loss in mPFC and hippocampus of MAM-exposed mice, extending from adolescence to adulthood. Moreover, the frequency of sIPSCs in pyramidal neurons at mPFC and hippocampus was significantly dampened in the 10 mg/kg and 15 mg/kg MAM-exposed mice. Furthermore, the firing rate of putative pyramidal neurons in mPFC and hippocampus was increased, while that of putative inhibitory neurons was decreased during both adolescence and adulthood. In conclusion, PV loss in mPFC and hippocampus of MAM-exposed mice may contribute to the impaired inhibitory function leading to the attenuation of inhibition in the brain both in vitro and in vivo.

Significance Statement PV neurons could play an important role in maintaining the balance of neural network homeostasis for its ability to provide strong inhibition. PV neurons were reduced in the mPFC and hippocampus in the schizophrenia patients. In this study, we demonstrated that 10 mg/kg and 15 mg/kg MAM exposure causes a loss of PV neurons in the mPFC and hippocampus of mice, which leads to an impaired inhibitory function. Overall, these results provided the significance of PV neurons modulating neural network homeostasis and involving in the pathogenesis of schizophrenia.