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Model Mice for Mild-Form Glycine Encephalopathy: Behavioral And 0031-3998/08/6403-0228 Vol. 64, No. 3, 2008 PEDIATRIC RESEARCH Printed in U.S.A. Copyright © 2008 International Pediatric Research Foundation, Inc. ARTICLES 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, AND YOICHI MATSUBARA Department of Medical Genetics [K.K.-I., S.K., A.I., T.S., A.N., S.K., J.K., F.K., Y.A., Y.M.], Department of Pediatrics [H.Y.], Tohoku University School of Medicine, Miyagi, 980-8574, Japan; Department of Neurosurgery [M.O., T.S., K.M.], Akita University School of Medicine, Akita, 010-8502, Japan; Department of Psychology [D.N.], Hamamatsu University School of Medicine, Shizuoka, 431-3192, Japan ABSTRACT: Glycine encephalopathy (GE) is caused by an inher- genase, which are encoded by GLDC, AMT, GCSH and GCSL, ited deficiency of the glycine cleavage system (GCS) and character- respectively (2). A defect of any component can lead to ized by accumulation of glycine in body fluids and various neuro- defective overall activity of the GCS. GLDC, AMT and GCSH logic symptoms. Coma and convulsions develop in neonates in mutations have been reported in GE patients (3,4). Patients typical GE while psychomotor retardation and behavioral abnormal- with typical GE have severe symptoms such as convulsions, ities in infancy and childhood are observed in mild GE. Recently, we have established a transgenic mouse line (low-GCS) with reduced respiratory failure and lethargy in the neonatal period, fre- GCS activity (29% of wild-type (WT) C57BL/6) and accumulation quently leading to death. Patients with mild GE do not expe- of glycine in the brain (Stroke, 2007; 38:2157). The purpose of the rience coma or convulsive seizures in the neonatal period, but present study is to characterize behavioral features of the low-GCS manifest developmental delay and behavioral abnormalities in mouse as a model of mild GE. Two other transgenic mouse lines infancy and childhood (5–7). They tend to be hyperirritable, were also analyzed: high-GCS mice with elevated GCS activity and hyperactive and aggressive characteristics, which are often low-GCS-2 mice with reduced GCS activity. As compared with problematic for their families. Patients with mild GE are controls, low-GCS mice manifested increased seizure susceptibility, thought to have increased susceptibility to seizures. Mild GE aggressiveness and anxiety-like activity, which resembled abnormal behaviors reported in mild GE, whereas high-GCS mice were less tends to be characterized by higher GCS residual activity than sensitive to seizures, hypoactive and less anxious. Antagonists for the typical GE (8,9). No effective therapy has been established for glycine-binding site of the N-methyl-D-aspartate receptor signifi- either typical or mild GE. cantly ameliorated elevated locomotor activity and seizure suscepti- Glycine is a major neurotransmitter, which plays a dual role bility in the low-GCS mice. Our results suggest the usefulness of in CNS. It acts on the inhibitory glycine receptor in spinal cord low-GCS mice as a mouse model for mild GE and a novel therapeutic and brainstem (10), as well as a coagonist of N-methyl-D- strategy. (Pediatr Res 64: 228–233, 2008) aspartate-sensitive (NMDA) glutamate receptors in the cortex, hippocampus, cerebellum and brainstem (11). Enzymatic ac- lycine encephalopathy (GE) is an inborn error of metab- tivity of the GCS is high in the forebrain and cerebellum and G olism characterized by glycine accumulation in plasma, low in the spinal cord, while the inhibitory glycine receptors cerebrospinal fluid and various organs including the brain (1). are mainly distributed in the brainstem and spinal cord, sug- The fundamental defect of GE lies in the mitochondrial gly- gesting that the GCS is co-localized with NMDA receptors cine cleavage system (GCS). The GCS is an enzyme complex, (12,13). Therefore, the GCS would play a role in regulation of which breaks down glycine to carbon dioxide, ammonia and extracellular glycine concentration in the vicinity of NMDA one-carbon units. The GCS is composed of four individual receptors, rather than the inhibitory glycine receptors. proteins: glycine decarboxylase (GLDC), aminomethyl trans- Recently, we generated a transgenic mouse line, designated ferase, aminomethyl carrier protein, and lipoamide dehydro- as low-GCS, expressing dominant-negative GLDC cDNA to reduce GCS activity (14). The low-GCS mouse has 29% of Received November 6, 2007; accepted April 3, 2008. normal GCS activity in CNS, and shows elevated glycine Corresponding Author: Shigeo Kure, M.D., Department of Medical Genetics, Tohoku concentration in extracellular fluid. A transgenic mouse line University School of Medicine, 1-1 Seiryomachi, Aobaku, Sendai, Miyagi, 980-8574, over expressing normal glycine decarboxylase cDNA, desig- Japan, Tel: ϩ81-22-717-8138, Fax: ϩ81-22-717-8142. e-mail: [email protected] Financial support: This work was supported by a grant from the Ministry of Education, Culture, Sports, Science, and Technology, Japan, and a grant from the Ministry of Health, Abbreviations: GCS, glycine cleavage system; GE, glycine encephalopathy; Labour, and Public Welfare in Japan. GLDC, glycine decarboxylase; NMDA, N-methyl-D-aspartate; 5-HT, serotonin 228 MILD GLYCINE ENCEPHALOPATHY MODEL MICE 229 nated as high-GCS, was also established, which showed ele- Experimental mice were kept in a controlled environment at 21 Ϯ 2°C and vated GCS activity and a lower extracellular concentration of 40–60% air humidity in a 12/12 h light/dark cycle with food and water ad libitum. C57BL/6 mice were purchased from Japan SLC Co. Ltd. glycine in CNS. Using these two mouse lines, we have found (Hamamatsu, Japan). Each transgenic mouse line was backcrossed with that ischemic injury depends on the extracellular level of C57BL/6 mice more than 10 generations and used for behavioral studies. glycine. We have also demonstrated that an antagonist for the Measurement of locomotor activity. The locomotor activity of the mice was measured by sensor, which detected infrared energy emitted by the mouse glycine site of the NMDA receptor significantly ameliorates (Supermex; Muromachi Kikai, Tokyo, Japan). The mice were placed in a the ischemic injury in low-GCS mice. novel test cage (30 ϫ 20 ϫ 13 cm) with paper-chip bedding, and measure- The purpose of this study is to characterize the behavioral ment was commenced 30 min later. Spontaneous locomotor activity of 6 to 8 wk-old female mice was measured for 24 h. Data were expressed as mean Ϯ features of the low-GCS mouse as a model for mild GE by SD and analyzed by one-way analysis of variance (ANOVA) with the post examining locomotor activity, seizure susceptibility, aggres- hoc Fisher’s PLSD test. siveness and anxiety-related behavior, which are reported as Seizure induced by an electroshock. Seizure susceptibility was evaluated by measuring the durations of each phase of convulsion induced by electro- behavioral features associated with patients with mild GE. We shock (15). The tonic phase was regarded as the period between the onset of compared the low-GCS mice not only with wild-type (WT) hind-limb extension and the beginning of myoclonic jerks, the clonic phase as C57BL/6 mice, but also with high-GCS mice and another that during myoclonic jerks and the convulsive coma phase as that between transgenic mouse line with low GCS activity designated as the the end of myoclonic jerks and the recovery of the righting reflex. Data were expressed as mean Ϯ SD and analyzed by one-way ANOVA with the post hoc low-GCS-2 mouse line. Results of an experimental therapy in Fisher’s PLSD test. which antagonists of the NMDA glutamate receptor were Resident-intruder test. A resident-intruder test has been developed for applied to those model mice suggest the possibility of a novel evaluation of male aggressiveness (16). Male mice, 12–18 wk of age (resi- dents) were kept isolated in separate cages for at least 2 wk. The home cages treatment of mild GE. of the resident mice were not changed during isolation. A group-housed Balb/c male mouse was used as an intruder. Residents were previously MATERIALS AND METHODS exposed to an intruder twice a week for a total of four 15-min confrontations. When an intruder was introduced into the home cage of the resident at the fifth This study was performed according to fundamental guidelines of proper confrontation, the latency to the first attack bite was noted and the total conduct of animal experiment and related activities in Academic Research number of attack bites was recorded for 15 min. A mouse that had had no Institutions of Japan. Animal experiment committee of Tohoku University previous contact with the resident was used as the intruder at each confron- School of Medicine approved this study (approval number, 8-26, 1998). tation. We defined latency less than 30s as short latency and more than 30 Transgenic mice. Establishment and characterization of two transgenic attacks as frequent attack. The proportion of short latency and frequent attacks mouse lines, high-GCS and low-GCS, have been previously reported (14). In in each mouse line was compared with that of the WT mice by Fisher’s exact this study we used another mouse line with transgenic expression of a test. dominant-negative GLDC, designated as low-GCS-2, which was established Elevated-plus maze. The elevated-plus maze test is widely used for by injection of the same transgenic vector with the low-GCS mouse (Fig.
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