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Publications

Journal Article Review Epublish 1 citation

PubMed: 42363168 DOI: 10.1186/s12987-026-00818-1

Convergent blood-brain barrier breakdown in schizophrenia and autism spectrum disorders: a systematic review of preclinical animal models.

Fluids Barriers CNS 23(1)

Authors: Cristina Morente-Montilla, María Fernández-Guillén, Ana Gómez-Garrido, Susana García-Cerro, Amanda Moreno-Mellado, Matthew Campbell, Hermona Soreq, David S Greenberg, Maria A Deli, Benedicto Crespo-Facorro, Celia Martín-Cuevas, Maurizio S Riga

Affiliations

  • Instituto de Biomedicina de Sevilla (IBiS)/University Hospital Virgen del Rocío/CSIC/University of Sevilla, Manuel Siurot AV, Seville, 41013, Spain. Spanish Network for Research in Mental Health (CIBERSAM, ISCIII), Monforte de Lemos AV, 3-5, Madrid, 28029, Spain.
  • Smurfit Institute of Genetics, Trinity College Dublin, Dublin, 2, Ireland.
  • FutureNeuro, Science Foundation Ireland Research Centre for Chronic and Rare Neurological Diseases, Royal College of Surgeons inIreland; University of Medicine and Health Sciences, Dublin, Ireland.
  • Edmond and Lily Safra Center for Brain Sciences, Hebrew University of Jerusalem, Jerusalem, Israel.
  • Department of Biological Chemistry, Alexander Silberman Institute of Life Sciences,Faculty of Mathematics and Science, Hebrew University of Jerusalem, Jerusalem, Israel.
  • Institute of Biophysics, HUN-REN BiologicalResearch Centre, Szeged, Hungary.
  • Instituto de Biomedicina de Sevilla (IBiS)/University Hospital Virgen del Rocío/CSIC/University of Sevilla, Manuel Siurot AV, Seville, 41013, Spain.
  • Spanish Network for Research in Mental Health (CIBERSAM, ISCIII), Monforte de Lemos AV, 3-5, Madrid, 28029, Spain.
  • Department of Psychiatry, School of Medicine, University of Seville, Manuel Siurot AV, Seville, 41013, Spain.
  • Instituto de Biomedicina de Sevilla (IBiS)/University Hospital Virgen del Rocío/CSIC/University of Sevilla, Manuel Siurot AV, Seville, 41013, Spain.
  • Spanish Network for Research in Mental Health (CIBERSAM, ISCIII), Monforte de Lemos AV, 3-5, Madrid, 28029, Spain.

Abstract

BACKGROUND

Schizophrenia (SCZ) and autism spectrum disorder (ASD) are neurodevelopmental disorders with multifactorial origins involving genetic and environmental risk factors. Both conditions share overlapping pathophysiological mechanisms, including neuroinflammation, synaptic dysfunction, and circuit-level disturbances. Emerging evidence implicates blood-brain barrier (BBB) dysfunction as a potential common element in their pathogenesis. Specifically, BBB disruption is a recurring feature in preclinical models of SCZ and ASD, suggesting its role as a transdiagnostic mechanism in neurodevelopmental disorders. This systematic review aims to evaluate BBB alterations-including permeability, integrity, developmental changes, and tight junction (TJ) protein expression-in rodent models of SCZ- and ASD-like phenotypes.

METHODS

Following PRISMA guidelines, we screened experimental studies assessing BBB status in murine models of SCZ and ASD compared to wild type rodents. Inclusion criteria focused on models based on genetic manipulation and environmental insults. Included studies consistently reported BBB alterations across diverse models.

RESULTS

Findings showed disrupted TJ protein expression (claudin-5, occludin, ZO-1), increased permeability, and endothelial dysfunction. Both genetic (e.g., Shank3, 22q11.2 deletion, etc.) and environmental (e.g., maternal immune activation, valproate exposure, etc.) models exhibited BBB abnormalities. Pharmacological and experimental interventions targeting the BBB-such as claudin-5 modulation or β-catenin signaling-ameliorated BBB damage and behavioral phenotypes.

CONCLUSIONS

That BBB disruption is a recurring feature in preclinical models of SCZ and ASD suggests its pursuit as a transdiagnostic mechanism in neurodevelopmental disorders. However, as many findings rely on single studies, further replication is essential. Future studies should explore sex differences, critical developmental windows, and therapeutic strategies aimed at restoring BBB function.

MeSH

Blood-Brain Barrier, Autism Spectrum Disorder, Blood, Brain, Phenotype, Neurodevelopmental Disorders, Autistic Disorder, Schizophrenia, Claudin-5, Claudins, Neurodevelopment