Disruption of Reelin signaling in a dual-hit mouse model of schizophrenia: impact of postnatal Δ9-tetrahydrocannabinol exposure in a poly(I:C) model

Since the introduction of dopamine D2 receptor antagonists, the pharmacological management of schizophrenia has remained largely centred on modulation of dopaminergic neurotransmission. However, substantial variability in therapeutic response highlights the need for improved biomarkers and alternative therapeutic targets. Environmental risk factors such as prenatal immune challenges and adolescent cannabis exposure have both been implicated in schizophrenia pathophysiology, yet their interaction remains incompletely understood. Reelin signalling has emerged as a relevant pathway in neurodevelopmental and psychiatric disorders, warranting further investigation in translational models.

The aim of this study was to establish and characterise a dual-hit mouse model combining maternal immune activation and adolescent cannabinoid exposure, and to evaluate its relevance for schizophrenia-related phenotypes and Reelin pathway alterations. Maternal immune activation was induced during gestation through administration of polyinosinic-polycytidylic acid, while adolescent mice were exposed to Δ9-tetrahydrocannabinol, the principal psychoactive constituent of cannabis. Behavioural assessments examined social interaction and repetitive behaviours. Structural analyses included cortical thickness measurements and dendritic spine density quantification in the prefrontal cortex and hippocampus. Molecular analyses assessed Reelin protein levels and the number of Reelin-positive cells. Statistical analyses were performed using two-way or three-way analysis of variance depending on the number of experimental groups and variables considered, followed by Tukey’s post hoc test. Statistical significance was set at p < 0.05.

The dual-hit condition produced behavioural alterations across multiple domains. Male mice displayed reduced social interaction compared with controls and increased repetitive behaviour, whereas females showed less pronounced behavioural changes. These findings indicate a sex-dependent vulnerability. Structural analyses revealed that adolescent Δ9-tetrahydrocannabinol exposure was associated with reduced cortical thickness relative to vehicle-treated controls. Dual-hit animals exhibited decreased dendritic spine density in both the prefrontal cortex and hippocampus, suggesting impaired synaptic organisation in regions linked to cognition and emotional regulation.

At the molecular level, alterations in the Reelin pathway were observed in a sex-dependent manner. In males, reduced Reelin levels were most evident following Δ9-tetrahydrocannabinol exposure alone, whereas females demonstrated a broader reduction across treatment groups. In addition, the number of Reelin-positive cells was significantly decreased in exposed groups compared with controls. These findings suggest that adolescent cannabinoid exposure is a major contributor to Reelin-related disruption, with prenatal immune activation modulating the specificity of these effects.

Overall, these findings indicate that adolescent THC exposure is a major driver of Reelin-related alterations, while prenatal immune activation may modulate the specificity and magnitude of these effects. This model selectively recapitulates relevant SCZ-associated phenotypes and highlights the complex, domain-specific interaction between environmental risk factors. Our results support a role for Reelin signaling alterations in schizophrenia-related processes, while emphasizing that their contribution depends on the nature and timing of environmental insults. These observations collectively reinforce the importance of considering both the timing and nature of environmental insults when modeling psychiatric disorders, and they further suggest that distinct developmental windows may shape vulnerability to specific behavioral, structural, and molecular outcomes relevant to schizophrenia across sexes and across experimental conditions consistently.

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