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

Greene, C, Kealy, J, Humphries, M M, Gong, Y, Hou, J, Hudson, N, Cassidy, L M, Martiniano, R, Shashi, V, Hooper, S R, Grant, G A, Kenna, P F, Norris, K, Callaghan, C K, Islam, M dN, O'Mara, S M, Najda, Z, Campbell, S G, Pachter, J S, Thomas, J, Williams, Nigel, Humphries, P, Murphy, K C and Campbell, M 2017. Dose-dependent expression of claudin-5 is a modifying factor in schizophrenia. Molecular Psychiatry 23 , pp. 2156-2166. 10.1038/mp.2017.156

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Abstract

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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher: Nature Publishing Group
ISSN: 1359-4184
Date of First Compliant Deposit: 20 October 2017
Date of Acceptance: 7 June 2017
Last Modified: 27 Feb 2019 13:48
URI: http://orca-mwe.cf.ac.uk/id/eprint/105780

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