Exploration for therapeutic strategy to improve working memory deficit in an animal model of schizophrenia under clinically relevant antipsychotic dose regimen

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K07925
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52030:Psychiatry-related
• Research Institution: Dokkyo Medical University
• Principal Investigator: Arime Yosefu 獨協医科大学, 医学部, 講師 (80609404)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: 統合失調症 / 動物モデル / 認知機能障害 / 前頭前野 / パルブアルブミン陽性抑制性神経 / 抗精神病薬 / 化学遺伝学 / in vivoイメージング

Outline of Final Research Achievements

Cognitive deficits in patients with schizophrenia, such as working memory, is critically important to functional outcomes, yet none produce meaningful improvements in cognitive deficits. In addition, their neurocircuit pathophysiology is not fully understood. In the present study, we have succeeded in ameliorating working memory deficit in mice chronically treated with phencyclidine (PCP) by chemogenetic activation of parvalbumin-positive interneurons in layers 2-3 of the prelimbic cortex, which we had identified as a candidate neural circuit responsible for the working memory deficit in mice chronically treated with PCP. More importantly, this improvement effect was also exhibited under chronic administration of antipsychotic drugs. These findings suggest a new therapeutic strategy to ameliorate cognitive deficits in schizophrenia and may assist in the development of future therapeutic agents.

Free Research Field

精神神経科学

Academic Significance and Societal Importance of the Research Achievements

統合失調症は多くが思春期から青年期に発症する慢性の精神疾患である。患者の機能的転帰に極めて重要であるにも関わらず有効な治療法のないアンメットメディカルニーズである。本研究で得られた成果は、統合失調症における前頭前野のパルブアルブミン陽性抑制性神経と認知機能障害の因果関係を支持する新たな証拠を提供するものである。加えて、前頭前野のパルブアルブミン陽性抑制性神経に対する摂動が抗精神病薬へのadd-on療法としても機能し、統合失調症の認知機能障害を改善することを目的とした創薬に新たな知見を提供する可能性がある。