10779/rcsi.10793960.v1 C Greene C Greene J Kealy J Kealy M M. Humphries M M. Humphries Y Gong Y Gong J Hou J Hou N Hudson N Hudson L M. Cassidy L M. Cassidy R Martiniano R Martiniano V Shashi V Shashi S R. Hooper S R. Hooper G A. Grant G A. Grant P F. Kenna P F. Kenna K Norris K Norris C K. Callaghan C K. Callaghan M D. Islam M D. Islam S M. O'Mara S M. O'Mara Z Najda Z Najda S G. Campbell S G. Campbell J S. Pachter J S. Pachter J Thomas J Thomas N M. Williams N M. Williams P Humphries P Humphries Kieran C. Murphy Kieran C. Murphy M Campbell M Campbell Dose-dependent expression of claudin-5 is a modifying factor in schizophrenia. Royal College of Surgeons in Ireland 2019 IR content Psychiatry (incl. Psychotherapy) 2019-11-22 17:07:33 Journal contribution https://repository.rcsi.com/articles/journal_contribution/Dose-dependent_expression_of_claudin-5_is_a_modifying_factor_in_schizophrenia_/10793960 <p>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.Molecular Psychiatry advance online publication, 10 October 2017; doi:10.1038/mp.2017.156.</p>