PMID- 30038322
OWN - NLM
STAT- MEDLINE
DCOM- 20191017
LR  - 20191017
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 8
IP  - 1
DP  - 2018 Jul 23
TI  - Hippocampal metabolism of amino acids by L-amino acid oxidase is involved in fear 
      learning and memory.
PG  - 11073
LID - 10.1038/s41598-018-28885-x [doi]
LID - 11073
AB  - 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.
FAU - Usuda, Kento
AU  - Usuda K
AD  - United Graduate School of Veterinarian Science, Gifu University, Gifu, Gifu, 
      Japan.
AD  - Laboratory of Veterinary Physiology, Department of Veterinary Medicine, Tokyo 
      University of Agriculture and Technology, Fuchu, Tokyo, Japan.
FAU - Kawase, Takahiro
AU  - Kawase T
AD  - Kyoto Institute of Nutrition and Pathology, Tsuzuki, Kyoto, Japan.
FAU - Shigeno, Yuko
AU  - Shigeno Y
AD  - Laboratory of Benno, RIKEN Innovation Center, Wako, Saitama, Japan.
FAU - Fukuzawa, Susumu
AU  - Fukuzawa S
AD  - Laboratory of Veterinary Physiology, Department of Veterinary Medicine, Tokyo 
      University of Agriculture and Technology, Fuchu, Tokyo, Japan.
FAU - Fujii, Kazuki
AU  - Fujii K
AD  - Life Science Research Center, Toyama University, Toyama, Toyama, Japan.
FAU - Zhang, Haolin
AU  - Zhang H
AD  - College of Biological Science and Technology, Beijing Forestry University, 
      Haidian, Beijing, China.
FAU - Tsukahara, Takamitsu
AU  - Tsukahara T
AUID- ORCID: 0000-0002-3902-5956
AD  - Kyoto Institute of Nutrition and Pathology, Tsuzuki, Kyoto, Japan.
FAU - Tomonaga, Shozo
AU  - Tomonaga S
AUID- ORCID: 0000-0003-0888-1407
AD  - Division of Applied Biosciences, Graduate School of Agriculture, Kyoto 
      University, Kyoto, Kyoto, Japan.
FAU - Watanabe, Gen
AU  - Watanabe G
AUID- ORCID: 0000-0001-7611-4678
AD  - United Graduate School of Veterinarian Science, Gifu University, Gifu, Gifu, 
      Japan.
AD  - Laboratory of Veterinary Physiology, Department of Veterinary Medicine, Tokyo 
      University of Agriculture and Technology, Fuchu, Tokyo, Japan.
FAU - Jin, Wanzhu
AU  - Jin W
AUID- ORCID: 0000-0002-5860-2958
AD  - Institute of Zoology, Chinese Academy of Sciences, Chaoyang, Beijing, China.
FAU - Nagaoka, Kentaro
AU  - Nagaoka K
AUID- ORCID: 0000-0003-1038-1380
AD  - United Graduate School of Veterinarian Science, Gifu University, Gifu, Gifu, 
      Japan. nagaokak@cc.tuat.ac.jp.
AD  - Laboratory of Veterinary Physiology, Department of Veterinary Medicine, Tokyo 
      University of Agriculture and Technology, Fuchu, Tokyo, Japan. 
      nagaokak@cc.tuat.ac.jp.
LA  - eng
GR  - JP26660248/Japan Society for the Promotion of Science (JSPS)/International
GR  - JP17K19797/Japan Society for the Promotion of Science (JSPS)/International
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180723
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (Amino Acids)
RN  - 0 (Neurotransmitter Agents)
RN  - 0 (RNA, Messenger)
RN  - EC 1.4.3.2 (L-Amino Acid Oxidase)
RN  - EC 2.7.1.40 (Pyruvate Kinase)
SB  - IM
MH  - Amino Acids/blood/*metabolism
MH  - Animals
MH  - *Fear
MH  - Gene Expression Regulation, Enzymologic
MH  - Hippocampus/enzymology/*metabolism
MH  - L-Amino Acid Oxidase/genetics/*metabolism
MH  - Male
MH  - *Memory
MH  - Metabolome
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Neurotransmitter Agents/metabolism
MH  - Pyruvate Kinase/genetics/metabolism
MH  - RNA, Messenger/genetics/metabolism
PMC - PMC6056520
COIS- The authors declare no competing interests.
EDAT- 2018/07/25 06:00
MHDA- 2019/10/18 06:00
PMCR- 2018/07/23
CRDT- 2018/07/25 06:00
PHST- 2017/09/06 00:00 [received]
PHST- 2018/07/02 00:00 [accepted]
PHST- 2018/07/25 06:00 [entrez]
PHST- 2018/07/25 06:00 [pubmed]
PHST- 2019/10/18 06:00 [medline]
PHST- 2018/07/23 00:00 [pmc-release]
AID - 10.1038/s41598-018-28885-x [pii]
AID - 28885 [pii]
AID - 10.1038/s41598-018-28885-x [doi]
PST - epublish
SO  - Sci Rep. 2018 Jul 23;8(1):11073. doi: 10.1038/s41598-018-28885-x.