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

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.