Dose-dependent expression of claudin-5 is a modifying factor in schizophrenia. Issue 11 (November 2018)

• Record Type: Journal Article
• Authors: Greene, C; Kealy, J; Humphries, M; Gong, Y; Hou, J; Hudson, N; Cassidy, L; Martiniano, R; Shashi, V; Hooper, S; Grant, G; Kenna, P; Norris, K; Callaghan, C; Islam, M; O'Mara, S; Najda, Z; Campbell, S; Pachter, J; Thomas, J; Williams, N; Humphries, P; Murphy, K; Campbell, M
• Is Part Of: Molecular psychiatry. Volume 23:Issue 11(2018)
• Page Start: 2156
• Page End: 2166
• Publication Date: 2018-11
• Subjects: Mental illness -- Periodicals; Molecular biology -- Periodicals; Neurosciences -- Periodicals; Maladies mentales -- Périodiques; Biologie moléculaire -- Périodiques; Neurosciences -- Périodiques; Psychiatry; Mental illness; Molecular biology; Neurosciences; Moleculaire biologie; Psychiatrie; Psychische stoornissen; Mental Disorders -- Periodicals; Molecular Biology -- Periodicals; Neurosciences -- Periodicals; Electronic journals; Periodicals; 616.89
• DOI: 10.1038/mp.2017.156
• Languages: English
• ISSNs: 1359-4184

Abstract

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 theclaudin-5 gene. Here, we show that a variant in theclaudin-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 expressionin vitro andin 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.