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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.

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