Partial Reelin Deficiency Modulates Behavioral and Prefrontal Effects of Mild Prenatal Poly(I:C) Exposure

Gene-environment interactions are thought to contribute to neurodevelopmental psychiatric disorders, yet their behavioral and molecular consequences remain incompletely understood. Here, we examined whether partial deficiency of reelin (Reln) increases susceptibility to a mild prenatal immune challenge in mice. Heterozygous Reln mice and wild-type littermates were exposed to low-dose polyinosinic-polycytidylic acid (Poly(I:C); 2 mg/kg, intraperitoneally) at embryonic day 12.5. Adult male offspring were assessed in the open-field, three-chamber social interaction, and marble-burying tests, followed by gene expression analysis in the medial prefrontal cortex (mPFC). In the open-field test, prenatal Poly(I:C) exposure was associated with increased locomotor activity during the late habituation phase, with the clearest increase in the combined-risk group. In the social interaction test, significant social novelty preference was not detected in the combined-risk group, whereas sociability toward an unfamiliar conspecific was preserved across groups. Marble-burying behavior was reduced in heterozygous Reln mice irrespective of immune challenge, suggesting a genotype-related behavioral alteration that was partly distinct from the combined-risk phenotype observed in the other tests. In the mPFC, several γ-aminobutyric acid A (GABA_A) receptor subunit transcripts were altered in a gene- and exposure-specific manner. Gabra2 expression was reduced in the combined-risk group, whereas Reln expression was decreased in heterozygous mice independent of immune challenge. These findings indicate that partial Reln deficiency provides a permissive genetic background in which mild prenatal immune activation subtly alters higher-order behavioral adaptation and prefrontal GABA_A-related gene expression.