Disruption of Reelin signaling in a dual-hit mouse model of schizophrenia: impact of postnatal Δ9-tetrahydrocannabinol exposure in a maternal immune activation model.

Since the discovery of the first antipsychotic, pharmacological treatment of schizophrenia (SCZ) has primarily relied on dopamine D2 receptor antagonist. However, variability in treatment responses highlights the need for novel biomarkers and therapeutics targets. Here, we developed a dual-hit mouse model combining maternal immune activation (MIA) induced by polyinosinic-polycytidylic acid (Poly(I:C)) with adolescent exposure to Δ9-tetrahydrocannabinol (THC), the main psychoactive component of cannabis. We evaluated the face validity of this model and investigated potential alterations in the Reelin signaling pathway. Behaviorally, the dual-hit condition induced alterations across multiple domains, including social deficits and increased repetitive behavior, consistent with schizophrenia-relevant phenotypes. These effects were particularly evident in males, supporting a domain-specific interaction between prenatal immune activation and adolescent THC exposure rather than a uniform synergistic effect. Structurally, THC exposure was associated with reduced cortical thickness, while dual-hit mice showed decreased dendritic spine density in the prefrontal cortex and hippocampus. At the molecular level, Reelin pathway alterations were observed in a sex-dependent manner. In males, reduced Reelin levels were most prominent following THC exposure alone, whereas in females, a general reduction was observed across treatment groups. Additionally, a decrease in the number of Reelin-positive cells was detected. These findings indicate that adolescent THC exposure is a major driver of Reelin alterations, with prenatal immune activation potentially modulating this effect. Overall, this model recapitulates selective SCZ-relevant phenotypes and highlights the complex, domain-specific interaction between environmental risk factors. Our results support a role for Reelin signaling alterations in SCZ-related processes, while emphasizing that their contribution depends on the nature and timing of environmental insults. Abbreviations: Poly(I:C): polyinosinic-polycytidylic acid; THC: Δ9-tetrahydrocannabinol; GD: gestational day; PD: postnatal day; PFC: prefrontal cortex; HP: hippocampus. Created with Biorender.com.