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

// Keisuke Nishiura 1,* , Naoki Ichikawa-Tomikawa 1,* , Kotaro Sugimoto 1 , Yasuto Kunii 2,3 , Korehito Kashiwagi 1 , Mizuko Tanaka 1 , Yuichi Yokoyama 4 , Mizuki Hino 2 , Takashi Sugino 5 , Hirooki Yabe 2 , Hitoshi Takahashi 4 , Akiyoshi Kakita 4 , Tetsuya Imura 1,6 and Hideki Chiba 1 1 Department of Basic Pathology, Fukushima Medical University School of Medicine, Fukushima, Japan 2 Department of Neuropsychiatry, Fukushima Medical University School of Medicine, Fukushima, Japan 3 Department of Psychiatry, Aizu Medical Center, Fukushima Medical University, Fukushima, Japan 4 Department of Pathology, Brain Research Institute, Niigata University, Niigata, Japan 5 Department of Diagnostic Pathology, Shizuoka Cancer Center, Shizuoka, Japan 6 Department of Surgical Pathology, Kyoto Prefectural University of Medicine, Kyoto, Japan * These authors contributed equally to this work Correspondence to: Hideki Chiba, email: // Keywords : blood-brain barrier; tight junction; claudin; protein kinase A; schizophrenia; Pathology Section Received : August 30, 2017 Accepted : October 04, 2017 Published : October 16, 2017 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.