Disruption of Reelin signaling in a dual-hit mouse model of schizophrenia: impact of postnatal Δ9-tetrahydrocannabinol exposure in a maternal immune activation model
Year: 2026
Type: article
Abstract: 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.
Source: Translational Psychiatry
Institutions: Consejo Superior de Investigaciones Científicas, Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío, Universidad de Sevilla, CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Universidad Complutense de Madrid, Research Institute Hospital 12 de Octubre, University of the Basque Country
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,290
Funders: Mylan, European Commission, Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía, Centro de Investigación Biomédica en Red de Salud Mental, Junta de Andalucía, H. Lundbeck A/S, Instituto de Salud Carlos III, European Regional Development Fund, Agencia Estatal de Investigación
Awards: G1069719224, G1341289430, Descifrando la interconexión del fenotipo de la glía y la activación del inflamasoma durante el desarrollo cerebral: búsqueda de mecanismos diana para el tratamiento de la esquizofrenia, G1914577137, G2262748287, G2673512141, G2681092883, G2770555601, G2929503057, G2941117352, G3480869486, G3681454997, G3934026761, G4042783231, G425668148, G4267043543, G451917667, G5967599077, G6139444944, Alteración de la barrera hematoencefálica en la esquizofrenia: bases moleculares de la vulnerabilidad o la resistencia, G6751643913, G7084143925, G8684520763, G927608369
OpenAlex ID: W4412754277