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. Islam
S M. O'Mara
Z Najda
S G. Campbell
J S. Pachter
J Thomas
N M. Williams
P Humphries
Kieran C. Murphy
M Campbell
10779/rcsi.10793960.v1
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>
2019-11-22 17:07:33
IR content
Psychiatry (incl. Psychotherapy)