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.
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.
Kojima-ishii
Kanako
K
Department of Medical Genetics, Tohoku University School of Medicine, Miyagi, Japan.
Kure
Shigeo
S
Ichinohe
Akiko
A
Shinka
Toshikatsu
T
Narisawa
Ayumi
A
Komatsuzaki
Shoko
S
Kanno
Junnko
J
Kamada
Fumiaki
F
Aoki
Yoko
Y
Yokoyama
Hiroyuki
H
Oda
Masaya
M
Sugawara
Taku
T
Mizoi
Kazuo
K
Nakahara
Daiichiro
D
Matsubara
Yoichi
Y
D000374:Aggression / Q000187:drug effects / Q000502:physiology; D000594:Amino Acid Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001007:Anxiety / Q000188:drug therapy / Q000503:physiopathology; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D001928:Brain Diseases, Metabolic / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology / Q000627:therapeutic use; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D005998:Glycine / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism*; D011760:Pyrrolidinones / Q000494:pharmacology / Q000627:therapeutic use; D015363:Quinolones / Q000494:pharmacology / Q000627:therapeutic use; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D012640:Seizures / Q000503:physiopathology; D014166:Transferases / Q000235:genetics / Q000378:metabolism*
D002352:Carrier Proteins; D018691:Excitatory Amino Acid Antagonists; D009097:Multienzyme Complexes; D011760:Pyrrolidinones; D015363:Quinolones; D016194:Receptors, N-Methyl-D-Aspartate; C064525:glycine cleavage system; D016291:Dizocilpine Maleate; D000594:Amino Acid Oxidoreductases; D014166:Transferases; C001369:1-hydroxy-3-amino-2-pyrrolidone; C094635:L 701324; D005998:Glycine