Scientists have discovered that abnormalities of blood vessels in the brain may play a major role in the development of schizophrenia.
The network of blood vessels in the brain regulates the transport of energy and materials in and out of the brain -- forming what is known as the blood-brain barrier (BBB). Scientists have discovered in the journal Molecular Psychiatry that abnormalities in the integrity of the BBB may be a critical component in the development of schizophrenia and other brain disorders.
People living with a chromosomal abnormality termed '22q11 deletion syndrome' (22q11DS) are 20 times more likely to develop schizophrenia. These people lack approximately 40-60 genes within a small region in one of the pairs of chromosome 22. A gene termed "Claudin-5" is located within this region, and it is changes in the levels of this component of the BBB that are associated with the presence of schizophrenia.
Authors 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. They also show that targeted adeno-associated virus-mediated suppression of claudin-5 in the mouse brain results in localized BBB disruption and behavioral changes.
Using an inducible ‘knockdown’ mouse model, authors further link claudin-5 suppression with psychosis through a distinct behavioral phenotype showing impairments in learning and memory, anxiety-like behavior 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, researchers 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.
The senior author said: "Our recent findings have, for the first time, suggested that schizophrenia is a brain disorder associated with abnormalities of brain blood vessels. The concept of tailoring drugs to regulate and treat abnormal brain blood vessels is a novel treatment strategy and offers great potential to complement existing treatments of this debilitating disease."
"While it is very well accepted that improving cardiovascular health can reduce the risk of stroke and heart attacks, we now believe that drugs aimed at improving cerebrovascular health may be an additional strategy to treating brain diseases in the future."
The scientists are the first to identify a molecular genetic component of the blood brain barrier with the development of schizophrenia.