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

C. Greene, J. Kealy, M. M. Humphries, Y. Gong, J. Hou, N. Hudson, L. M. Cassidy, R. Martiniano, V. Shashi, S. R. Hooper, G. A. Grant, P. F. Kenna, K. Norris, C. K. Callaghan, M. d.N. Islam, S. M. O’Mara, Z. Najda, S. G. Campbell, J. S. Pachter, J. ThomasN. M. Williams, P. Humphries, K. C. Murphy, M. Campbell

Research output: Contribution to journalArticle

39 Scopus citations

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.

Original languageEnglish
Pages (from-to)2156-2166
Number of pages11
JournalMolecular Psychiatry
Volume23
Issue number11
DOIs
StatePublished - Nov 1 2018

Fingerprint Dive into the research topics of 'Dose-dependent expression of claudin-5 is a modifying factor in schizophrenia'. Together they form a unique fingerprint.

Cite this