Dose-dependent expression of claudin-5 is a modifying factor in schizophrenia.
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.
This work was supported by grants from Science Foundation Ireland (SFI), (12/YI/B2614 and 11/PI/1080), The Health Research Board of Ireland (HRB) and the BrightFocus Foundation. We thank the Stanley Medical Research Institute for providing post-mortem brain tissues used in this study. We thank Caroline Woods and Charles Murray for animal husbandry and Dr Julie Kelly for assistance with the RotaRod apparatus. We also thank Mr Rick Guidotti for providing the photographs used in Figure 1a as part of the ‘Positive Exposure’ initiative. Finally, we also thank Maciej M Jankowski for assistance in designing and building the PPI hardware.
CommentsThis article is also available at https://www.nature.com/mp/journal/vaop/ncurrent/pdf/mp2017156a.pdf
Published CitationGreene C, Kealy J, Humphries MM, Gong Y, Hou J, Hudson N, Cassidy LM, Martiniano R, Shashi V, Hooper SR, Grant GA, Kenna PF, Norris K, Callaghan CK, Islam MD, O'Mara SM, Najda Z, Campbell SG, Pachter JS, Thomas J, Williams NM, Humphries P, Murphy KC, Campbell M. Dose-dependent expression of claudin-5 is a modifying factor in schizophrenia. Molecular Psychiatry. 2017 [Epub ahead of print]