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Greene, 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, Callagha, CK, Islam, MN, O'Mara, SM, Najda, Z, Campbell, SG, S Pachter, J, Thomas, J , Williams, NM, Humphries, P, Murphy, KC and Campbell, M (2018) Dose-dependent expression of claudin-5 is a modifying factor in schizophrenia. MOLECULAR PSYCHIATRY, 23 (11). pp. 2156-2166. ISSN 1359-4184
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Dose-dependent expression of claudin-5 is a modifying factor in schizophrenia.pdf - Published Version Available under License Creative Commons Attribution. Download (5MB) | Preview |
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 |
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| Uncontrolled Keywords: | 06 Biological Sciences, 11 Medical and Health Sciences, 17 Psychology and Cognitive Sciences |
| Subjects: | Q Science > QH Natural history > QH301 Biology Q Science > QH Natural history > QH426 Genetics R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry |
| Divisions: | Biological & Environmental Sciences (from Sep 19) |
| Publisher: | NATURE PUBLISHING GROUP |
| Related URLs: | |
| Date Deposited: | 15 Jul 2020 09:32 |
| Last Modified: | 04 Sep 2021 07:00 |
| DOI or ID number: | 10.1038/mp.2017.156 |
| URI: | https://researchonline.ljmu.ac.uk/id/eprint/13306 |
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