Model mice for mild-form glycine encephalopathy: Behavioral and biochemical characterizations and efficacy of antagonists for the glycine binding site of N-methyl D-aspartate receptor

Kanako Kojima-Ishii, Shigeo Kure, Akiko Ichinohe, Toshikatsu Shinka, Ayumi Narisawa, Shoko Komatsuzaki, Junnko Kanno, Fumiaki Kamada, Yoko Aoki, Hiroyuki Yokoyama, Masaya Oda, Taku Sugawara, Kazuo Mizoi, Daiichiro Nakahara, Yoichi Matsubara

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4 Citations (Scopus)

Abstract

Glycine encephalopathy (GE) is caused by an inherited deficiency of the glycine cleavage system (GCS) and characterized by accumulation of glycine in body fluids and various neurologic symptoms. Coma and convulsions develop in neonates in typical GE while psychomotor retardation and behavioral abnormalities in infancy and childhood are observed in mild GE. Recently, we have established a transgenic mouse line (low-GCS) with reduced GCS activity (29% of wild-type (WT) C57BL/6) and accumulation of glycine in the brain (Stroke, 2007; 38:2157). The purpose of the present study is to characterize behavioral features of the low-GCS mouse as a model of mild GE. Two other transgenic mouse lines were also analyzed: high-GCS mice with elevated GCS activity and low-GCS-2 mice with reduced GCS activity. As compared with controls, low-GCS mice manifested increased seizure susceptibility, aggressiveness and anxiety-like activity, which resembled abnormal behaviors reported in mild GE, whereas high-GCS mice were less sensitive to seizures, hypoactive and less anxious. Antagonists for the glycine-binding site of the N-methyl-D-aspartate receptor significantly ameliorated elevated locomotor activity and seizure susceptibility in the low-GCS mice. Our results suggest the usefulness of low-GCS mice as a mouse model for mild GE and a novel therapeutic strategy.

Original languageEnglish
Pages (from-to)228-233
Number of pages6
JournalPediatric Research
Volume64
Issue number3
DOIs
Publication statusPublished - 2008 Sep

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health

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    Kojima-Ishii, K., Kure, S., Ichinohe, A., Shinka, T., Narisawa, A., Komatsuzaki, S., Kanno, J., Kamada, F., Aoki, Y., Yokoyama, H., Oda, M., Sugawara, T., Mizoi, K., Nakahara, D., & Matsubara, Y. (2008). Model mice for mild-form glycine encephalopathy: Behavioral and biochemical characterizations and efficacy of antagonists for the glycine binding site of N-methyl D-aspartate receptor. Pediatric Research, 64(3), 228-233. https://doi.org/10.1203/PDR.0b013e3181799562