Disruption of Reelin signaling in a dual-hit mouse model of schizophrenia: impact of postnatal Δ9-tetrahydrocannabinol exposure in a maternal immune activation model
Translational Psychiatry July 16, 2026 Celia Martín-Cuevas, Víctor Darío Ramos‐Herrero, Álvaro Flores‐Martínez et al.
A dual-hit mouse model combining prenatal immune activation with adolescent THC exposure produces schizophrenia-relevant behavioral and brain changes, particularly in males. Social deficits and repetitive behaviors emerged, along with reduced cortical thickness and decreased dendritic spine density in the prefrontal cortex and hippocampus. Reelin signaling pathway alterations occurred in a sex-dependent manner: males showed reduced Reelin levels mainly after THC exposure alone, while females had general reductions across treatment groups. The number of Reelin-positive cells also decreased. Adolescent THC exposure appears to be a major driver of Reelin alterations, with prenatal immune activation potentially modulating this effect. The findings highlight complex, domain-specific interactions between environmental risk factors in schizophrenia-related processes.