Hippocampal metabolism of amino acids by L-amino acid oxidase is involved in fear learning and memory

• Usuda, Kento

  United Graduate School of Veterinarian Science, Gifu University・Laboratory of Veterinary Physiology, Department of Veterinary Medicine, Tokyo University of Agriculture and Technology

• Kawase, Takahiro

  Kyoto Institute of Nutrition and Pathology

• Shigeno, Yuko

  Laboratory of Benno, RIKEN Innovation Center

• Fukuzawa, Susumu

  Laboratory of Veterinary Physiology, Department of Veterinary Medicine, Tokyo University of Agriculture and Technology

• Fujii, Kazuki

  Life Science Research Center, Toyama University

• Zhang, Haolin

  College of Biological Science and Technology, Beijing Forestry University

• Tsukahara, Takamitsu

  Kyoto Institute of Nutrition and Pathology

• Tomonaga, Shozo

  Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University

• Watanabe, Gen

  United Graduate School of Veterinarian Science, Gifu University・Laboratory of Veterinary Physiology, Department of Veterinary Medicine, Tokyo University of Agriculture and Technology

• Jin, Wanzhu

  Institute of Zoology, Chinese Academy of Sciences

• Nagaoka, Kentaro

  United Graduate School of Veterinarian Science, Gifu University・Laboratory of Veterinary Physiology, Department of Veterinary Medicine, Tokyo University of Agriculture and Technology

Abstract

Amino acids participate directly and indirectly in many important biochemical functions in the brain. We focused on one amino acid metabolic enzyme, L-amino acid oxidase (LAO), and investigated the importance of LAO in brain function using LAO1 knockout (KO) mice. Compared to wild-type mice, LAO1 KO mice exhibited impaired fear learning and memory function in a passive avoidance test. This impairment in LAO1 KO mice coincided with significantly reduced hippocampal acetylcholine levels compared to wild-type mice, while treatment with donepezil, a reversible acetylcholine esterase inhibitor, inhibited this reduction. Metabolomic analysis revealed that knocking out LAO1 affected amino acid metabolism (mainly of phenylalanine [Phe]) in the hippocampus. Specifically, Phe levels were elevated in LAO1 KO mice, while phenylpyruvic acid (metabolite of Phe produced largely by LAO) levels were reduced. Moreover, knocking out LAO1 decreased hippocampal mRNA levels of pyruvate kinase, the enzymatic activity of which is known to be inhibited by Phe. Based on our findings, we propose that LAO1 KO mice exhibited impaired fear learning and memory owing to low hippocampal acetylcholine levels. Furthermore, we speculate that hippocampal Phe metabolism is an important physiological mechanism related to glycolysis and may underlie cognitive impairments, including those observed in Alzheimer’s disease.

Journal

• Scientific Reports

  Scientific Reports 8 2018-07-23

  Springer Nature

Details

• CRID: 1050282813184406144
• NII Article ID: 120006522881
• ISSN: 20452322
• HANDLE: 2433/234566
• Text Lang: en
• Article Type: journal article
• Data Source:
  • IRDB
  • CiNii Articles