Environmental risk reshapes high-confidence schizophrenia risk genes during a developmental window of vulnerability

Abstract

Rare coding variants and environmental exposures such as early-life stress contribute to schizophrenia risk, but whether environmental adversity alters the expression of genetically implicated genes remains unclear. Combining the limited bedding and nesting (LBN) model of early-life stress (ELS) with 24-plex single-cell mFISH registered to the Allen Mouse Brain Atlas, we profiled the ten genes identified in the original SCHEMA study, the complement gene C4b and activity markers in 1.29 million cells across four postnatal ages. Whole-brain risk-gene upregulation was greatest at postnatal day 21 (P21), with region- and cell-type-selective effects that prominently involved the hypothalamus. Sp4 and Cacna1g showed distinct temporal responses: Sp4 increased at P21 and decreased at P90 in hypothalamic oligodendrocytes, whereas Cacna1g decreased at P10. ELS-associated C4b upregulation extended across neuronal and glial populations, including oligodendrocytes and OPCs. Across regional cell types, P10 C4b effects were positively correlated with P21 Grin2a effects. These findings suggest that ELS perturbs the developmental expression of genes implicated in schizophrenia, identifying potential molecular links between environmental adversity and genetic vulnerability.