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Mol Psychiatry. 2018 Nov;23(11):2156-2166. doi: 10.1038/mp.2017.156. Epub 2017 Oct 10.

Dose-dependent expression of claudin-5 is a modifying factor in schizophrenia.

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Department of Genetics, Smurfit Institute of Genetics, Lincoln Place Gate, Trinity College Dublin, Dublin, Ireland.
Division of Renal Diseases, Department of Internal Medicine, Washington University School of Medicine, St Louis, MO, USA.
Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.
Department of Allied Health Sciences, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA.
Biosciences Department, Faculty of Health and Wellbeing, Biosciences and Chemistry, Sheffield Hallam University, Sheffield, UK.
Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.
School of Psychology, Trinity College Dublin, Dublin, Ireland.
Department of Cell Biology, University of Connecticut Health Center, Farmington, CT, USA.
Department of Psychological Medicine and Neurology, MRC Centre in Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, UK.
Department of Psychiatry, Royal College of Surgeons in Ireland, Dublin, Ireland.
Department of Genetics, Smurfit Institute of Genetics, Lincoln Place Gate, Trinity College Dublin, Dublin, Ireland.


Schizophrenia is a neurodevelopmental disorder that affects up to 1% of the general population. Various genes show associations with schizophrenia and a very weak nominal association with the tight junction protein, claudin-5, has previously been identified. Claudin-5 is expressed in endothelial cells forming part of the blood-brain barrier (BBB). Furthermore, schizophrenia occurs in 30% of individuals with 22q11 deletion syndrome (22q11DS), a population who are haploinsufficient for the claudin-5 gene. Here, we show that a variant in the claudin-5 gene is weakly associated with schizophrenia in 22q11DS, leading to 75% less claudin-5 being expressed in endothelial cells. We also show that targeted adeno-associated virus-mediated suppression of claudin-5 in the mouse brain results in localized BBB disruption and behavioural changes. Using an inducible 'knockdown' mouse model, we further link claudin-5 suppression with psychosis through a distinct behavioural phenotype showing impairments in learning and memory, anxiety-like behaviour and sensorimotor gating. In addition, these animals develop seizures and die after 3-4 weeks of claudin-5 suppression, reinforcing the crucial role of claudin-5 in normal neurological function. Finally, we show that anti-psychotic medications dose-dependently increase claudin-5 expression in vitro and in vivo while aberrant, discontinuous expression of claudin-5 in the brains of schizophrenic patients post mortem was observed compared to age-matched controls. Together, these data suggest that BBB disruption may be a modifying factor in the development of schizophrenia and that drugs directly targeting the BBB may offer new therapeutic opportunities for treating this disorder.

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