Schizophrenia of blood vessel abnormalities in schizophrenia,

Schizophrenia is
a debilitating neuropsychiatric disorder, characterized by profound distortions
in cognition and emotion. Current research proposes the etiology of
schizophrenia as an interplay of genetic and environmental factors. This study,
unlike many previous researches, examines the potential significant role of
blood vessel abnormalities in schizophrenia, focusing on claudin-5 expressed in
endothelial cells of the blood-brain barrier (BBB).

chromosomal abnormality 22q11 deletion syndrome (22q11DS) patients had been
previously found with a 30-fold increased risk of schizophrenia. This condition
is due to microdeletion of ~40 genes in a small region of chromosome 22, where
claudin-5 is located. Through genotyping of 22q11SD patients for claudin-5
variant rs10314 in this study, this claudin-5 variant was found to weakly
associate with schizophrenia in 22q11DS patients, causing up to 75% decreased
claudin-5 expression at their BBB compared to general population.

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investigate site-specific suppression of claudin-5, adeno-associated virus
(AAV) expressing either shRNA against claudin-5 or a non-targeting control were
injected bilaterally into the hippocampus or medial prefrontal cortex (mPFC) of
mice, followed by administration of doxycycline to maximize suppression of
claudin-5. Claudin-5 levels were significantly suppressed in microvasculature
of both the hippocampus and mPFC in claudin-5 AAV-injected group. Intriguingly,
this suppression also led to significant behavioral changes in social and
learning & memory domain.

claudin-5 deficient mice die shortly after birth, an induced knockout mouse
model was generated to further investigate linkage of claudin-5. A gene
containing doxycycline-inducible claudin-5 shRNA was inserted into the mice.

When administered with doxycycline, claudin-5 level is significantly decreased
in the mice’s brain. The claudin-5 suppression led to onset of
schizophrenia-like characteristics, specifically significant impairments in
learning & memory, anxiety-like behavior and sensorimotor gating. Inducible
claudin-5 mice also developed seizures and died within 40 days.

the effects of common antipsychotic drugs (lithium, haloperidol and
chlorpromazine) on claudin-5 levels were examined both in vivo in wild-type c57/BL6 mice and in vitro in primary brain endothelial cell cultures. These drugs
were found to significantly increase claudin-5 protein level dose-dependently in vivo and in vitro, while significant increasing protein expression only in vivo.

study suggests the crucial role claudin-5 could possibly play in the development
of schizophrenia, and reinforces the importance of claudin-5 in neurological
functioning. Combined with findings of anti-psychotic drugs regulating BBB
integrity via claudin-5 levels, this paper offers a new promising approach to
developing more targeted treatments, with claudin-5 as a potential therapeutic
target for schizophrenia. 


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