Abstract
Schizophrenia is thought to be caused by a combination of genetic and environmental factors; however, its pathogenesis remains largely unknown. Here, we focus on the endothelial tight-junction protein claudin-5 (CLDN5), because the CLDN5 gene is mapped to the schizophrenia-associated 22q11.2 deletion region, and a single nucleotide polymorphism in the CLDN5 locus is also linked to schizophrenia. We show, by RT-qPCR and immunohistochemistry, that the expressions of CLDN5 mRNA and protein are significantly increased and decreased, respectively, in the schizophrenic prefrontal cortex (PFC) compared with control PFC. These changes were not observed in the schizophrenic visual cortex (VC), and neither the density nor diameter of the CD34-positive microvessels was altered in the schizophrenic PFC or VC. Interestingly, protein kinase A (PKA) was activated in the microvascular and perivascular regions of the schizophrenic PFC, and the pPKA-positive microvascular endothelial cells occasionally exhibited focal loss of CLND5. Since we previously demonstrated that cAMP induced CLDN5 mRNA expression and size-selective loosening of the endothelial barrier in PKA-independent and -dependent manners, respectively, a similar mechanism could contribute to the discrepancy between mRNA and protein expression of CLDN5 in the schizophrenic PFC. Taken collectively, these findings provide novel insights into the pathophysiology of schizophrenia.
Highlights
Schizophrenia is a complex psychotic disorder with an estimated prevalence of nearly 1% [1]
We previously showed that cAMP activated protein kinase A (PKA) to phosphorylate Cldn5 protein in cultured porcine and rat endothelial cells, resulting in size-selective loosening of the endothelial barrier, and that it simultaneously elevated the levels of Cldn5 mRNA in a PKA-independent manner [27, 28]
A close relationship between the diminished CLDN5 expression in Brain microvascular endothelial cells (BMVECs) and the blood-brain barrier (BBB) breakdown has been reported in a range of human neurological disorders [14, 15, 17, 18]
Summary
Schizophrenia is a complex psychotic disorder with an estimated prevalence of nearly 1% [1]. One of the strongest established genetic risk factors is the 22q11.2 microdeletions that cause 22q11.2 deletion syndrome ( known as velocardiofacial syndrome or DiGeorge syndrome) [4,5,6]. Genetic and environmental factors increase the risk of schizophrenia [10,11,12], the pathophysiology remains poorly understood. Brain microvascular endothelial cells (BMVECs) possessing well-developed tight junctions are primarily critical for the BBB, though the surrounding components, such as pericytes, astrocytic endfeet, and basement membranes that consist of various extracellular matrix proteins, contribute to the establishment of the BBB [13,14,15,16]. Breakdown of the BBB has been reported in various neurological disorders, including brain ischemic stroke, edema, infections, epilepsy, multiple sclerosis, Alzheimer’s disease, and Parkinson’s disease [14, 15, 17, 18]
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