Dataset Information

PKA activation and endothelial claudin-5 breakdown in the schizophrenic prefrontal cortex.

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.

SUBMITTER: Nishiura K

PROVIDER: S-EPMC5706803 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Publications

PKA activation and endothelial claudin-5 breakdown in the schizophrenic prefrontal cortex.

Nishiura Keisuke K Ichikawa-Tomikawa Naoki N Sugimoto Kotaro K Kunii Yasuto Y Kashiwagi Korehito K Tanaka Mizuko M Yokoyama Yuichi Y Hino Mizuki M Sugino Takashi T Yabe Hirooki H Takahashi Hitoshi H Kakita Akiyoshi A Imura Tetsuya T Chiba Hideki H

Oncotarget 20171016 55

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 <i>CLDN5</i> gene is mapped to the schizophrenia-associated 22q11.2 deletion region, and a single nucleotide polymorphism in the <i>CLDN5</i> locus is also linked to schizophrenia. We show, by RT-qPCR and immunohistochemistry, that the expressions of CLDN5 mRNA and pr ...[more]

PMID: 29212157

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Project description:Neural adhesion proteins are crucial in the development and maintenance of functional neural connectivity. Growing evidence suggests that the IgLON family of neural adhesion molecules LSAMP, NTM, NEGR1, and OPCML are important candidates in forming the susceptibility to schizophrenia (SCZ). IgLON proteins have been shown to be involved in neurite outgrowth, synaptic plasticity and neuronal connectivity, all of which have been shown to be altered in the brains of patients with the diagnosis of schizophrenia. Here we optimized custom 5'-isoform-specific TaqMan gene-expression analysis for the transcripts of human IgLON genes to study the expression of IgLONs in the dorsolateral prefrontal cortex (DLPFC) of schizophrenic patients (n = 36) and control subjects (n = 36). Uniform 5'-region and a single promoter was confirmed for the human NEGR1 gene by in silico analysis. IgLON5, a recently described family member, was also included in the study. We detected significantly elevated levels of the NEGR1 transcript (1.33-fold increase) and the NTM 1b isoform transcript (1.47-fold increase) in the DLPFC of schizophrenia patients compared to healthy controls. Consequent protein analysis performed in male subjects confirmed the increase in NEGR1 protein content both in patients with the paranoid subtype and in patients with other subtypes. In-group analysis of patients revealed that lower expression of certain IgLON transcripts, mostly LSAMP 1a and 1b, could be related with concurrent depressive endophenotype in schizophrenic patients. Additionally, our study cohort provides further evidence that cannabis use may be a relevant risk factor associated with suicidal behaviors in psychotic patients. In conclusion, we provide clinical evidence of increased expression levels of particular IgLON family members in the DLPFC of schizophrenic patients. We propose that alterations in the expression profile of IgLON neural adhesion molecules are associated with brain circuit disorganization in neuropsychiatric disorders, such as schizophrenia. In the light of previously published data, we suggest that increased level of NEGR1 in the frontal cortex may serve as molecular marker for a wider spectrum of psychiatric conditions.

Dataset Information

PKA activation and endothelial claudin-5 breakdown in the schizophrenic prefrontal cortex.

Publications

PKA activation and endothelial claudin-5 breakdown in the schizophrenic prefrontal cortex.

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