Regulation of blood-brain barrier by neuro-vascular units and the involvement in schizophrenia

2018 Fiscal Year Final Research Report

• Project/Area Number: 17K17979
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Human pathology; Nerve anatomy/Neuropathology
• Research Institution: Fukushima Medical University
• Principal Investigator: Nishiura Keisuke 福島県立医科大学, 医学部, 研究員 (30791024)
• Research Collaborator: Chiba Hideki ; Sugimoto Kotaro ; Tomikawa Naoki ; Takahashi hitoshi ; Kakita Akiyoshi
• Project Period (FY): 2017-04-01 – 2019-03-31
• Keywords: 神経血管ユニット / 血液脳関門 / 統合失調症 / クローディン / PKA / セロトニン / モノアミン / 血管内皮

Outline of Final Research Achievements

We found that the serotonin receptor 5-HT1A is strongly expressed in microvascular endothelial cells and pericyte. Using a novel co-culture system of these cells, we showed that serotonin/5-HT1A signaling regulates endothelial claudin-5 (CLDN5) expression. On the other hand, protein kinase A (PKA) was activated in the microvascular and perivascular regions of the schizophrenic prefrontal cortex (PFC), and the pPKA-positive microvascular endothelial cells occasionally showed focal loss of CLDN5. These alterations were brain-region selective, and not observed in normal brain. Thus, serotonin/5-HT1A/cAMP/PKA signaling contributes to
regulate endothelial CLDN5 expression and blood-brain barrier in brain-site specific manners.

Free Research Field

病理学

Academic Significance and Societal Importance of the Research Achievements

統合失調症ではセロトニン仮説等が提唱されているが、その病態は不明である。代表者は統合失調症前頭前野の微小血管選択的にprotein kinase A (PKA)が活性化し、その部位に一致して血液脳関門構成分子であるclaudin-5 (CLDN5)が部分消失していることを発見した。また5-HTが5-HT1A受容体を介して血液脳関門を制御する新規機構を発見した。セロトニン/5-HT1A/cAMP/PKAシグナルの破綻が統合失調症の病態に関与する可能性が示された。