Maternal fasting during early gestation induces epigenetic alterations and schizophrenia-related phenotypes

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Abstract
Schizophrenia is a severe neurodevelopmental disorder whose etiology remains incompletely understood. Epidemiological studies of the Dutch Hunger Winter demonstrated that maternal famine during early gestation increased the risk of schizophrenia in offspring, implicating the Developmental Origins of Health and Disease (DOHaD) framework. However, the molecular mechanisms underlying this association remain unclear. Here, we developed a novel DOHaD-based schizophrenia model by subjecting pregnant mice to transient fasting restricted to the peri-implantation period, a critical window of global epigenomic reprogramming. Male offspring of fasted dams exhibited schizophrenia-related phenotypes, including impaired sensorimotor gating, abnormal behavioral patterns, and reduced dendritic spine density in the medial prefrontal cortex. Multi-omics profiling, integrating bulk RNA sequencing, Visium HD spatial transcriptomics, and DNA methylation arrays, revealed convergent alterations in synaptic organization, protein homeostasis, and oxidative stress pathways. These findings highlight how brief maternal fasting reprograms the epigenome and reshapes neural circuitry. Our work establishes the first animal model that directly mirrors early gestational famine exposure linked to schizophrenia risk, providing a unique platform for uncovering epigenetic mechanisms underlying the developmental origins of psychiatric disorders.

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