Research reportImpaired cognitive performance in ornithine transcarbamylase-deficient mice on arginine-free diet
Introduction
Congenital deficiency of ornithine transcarbamylase (OTC) is the most common error of urea synthesis in man [15]. The animal model for OTC deficiency, the sparse-fur (spf) mouse [5], displays many of the metabolic hallmarks of the disorder [16], [17], [18]. Decreased nitrogen excretion capacity and other metabolic changes are responsible for altered nitrogenous compound levels, including hyperammonaemia and decreased plasma arginine concentrations [2], [17], [18]. Genetically, the spf mutation was shown to be X-linked [20], and to be due to a single amino acid substition in the OTC gene [23]. The spf model has been used in the study of the pathophysiology of OTC deficiency [4], [16], [17], [18], and it has been proposed as a useful model in the development of gene therapeutic approaches for human OTC deficiency [3].
Cognitive abnormalities are among the typical features in patients with urea cycle disorders [12], [14], [15]. Forty percent of OTC deficient children examined by Msall et al. [14] had an IQ below 70; and all cases of neonatal onset OTC deficiency, recently examined by Maestri et al. [12], showed severe developmental delay. Ammonia neurotoxicity is often considered to be the main mechanism underlying the unfavourable neurologic outcome in OTC deficiency, and other inborn errors of urea synthesis [12], [14], [15]. In this study, clinically stable spf and control mice were behaviourally tested under normal [Arg(+)] and hyperammonaemia-provoking arginine-free [Arg(−)] diet conditions. Cognitive functions were assessed using two learning tasks: the step-through, passive avoidance test and the Morris-type water maze. As an indicator of the metabolic status of the animals, plasma ammonia levels were determined in similarly treated animals. Behavioural assessment may further characterise the spf model, and provide feasible outcome measures for therapeutic experiments.
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Animals
Homozygous spf/spf breeder females of the CD1 strain were obtained from the Montreal colony. All experiments were performed in pigmented CD1×C57BL/6J F1 hybrids. Male spf/Y, female spf/spf and wild-type control males and females were housed under standard laboratory conditions (food and water ad libitum, 12/12 h dark–light cycle, normal room temperature and humidity), and used for experiments at 8–10 weeks of age. As also observed by DeMars et al. [5] in mice of a mostly C57BL background, our
Results
Prior to diet manipulation, plasma ammonia levels were already significantly higher in spf mice compared to controls (two-tailed t-test; P=0.003; Fig. 1). The baseline plasma ammonia level was almost four times higher in spf mice. Groups of spf and control animals were subjected to the same diet protocol as used for the water maze experiments (see below). Levels were analysed on experimental days 1 through 8 in groups of 6–11 animals. Animals started Arg(−) diet, three days before experimental
Discussion
The spf mutant mouse is a model for OTC deficiency, the most common inborn error of urea synthesis in man. We described the performance of clinically stable, adult spf mice on passive avoidance and water maze tests, and examined the effect of Arg(−) diet on their performance. The results show no evidence for impaired learning abilities in our spf mice on a normal Arg(+) diet. Batshaw et al. [3] did show slightly impaired passive avoidance retention in spf/Y males of the CD1 background. This
Acknowledgements
We thank Ilse Possemiers and Frieda Franck for technical assistance. Financial support was provided by Born-Bunge Foundation, University of Antwerp, OCMW-Antwerp Medical Research Foundation, NeuroSearch Antwerp, and FWO Grant No. G.0027.97 (to PPDD, RD and BM). RD is a Postdoctoral Fellow of the FWO-Flanders Scientific Fund.
References (24)
- et al.
Learning in a 14-unit T-maze is impaired in rats following systemic treatment with NW-nitro-L-arginine
Eur. J. Pharmacol.
(1998) - et al.
Intracerebroventricular injection of NW-nitro-L-arginine in rats impairs learning in a 14-unit T-maze
Eur. J. Pharmacol.
(1998) - et al.
Accumulation of large neutral amino acids in the brain of sparse-fur mice at hyperammonemic state
Biochem. Med. Metab. Biol.
(1987) - et al.
Neonatal onset ornithine transcarbamylase deficiency: a retrospective analysis
J. Pediatr.
(1999) - et al.
Impaired learning in rats in a 14-unit T-maze by 7-nitroindazole, a neuronal nitric oxide synthase inhibitor, is attenuated by the nitric oxide donor, molsidomine
Eur. J. Pharmacol.
(1998) - et al.
Arginine-related guanidino compounds and nitric oxide synthase in the brain of ornithine trnascarbamylase deficient spf mutant mouse: effect of metabolic arginine deficiency
Neurosci. Lett.
(1996) - et al.
The role of nitric oxide in passive avoidance learning
Neuropharmacology
(1997) Treatment of urea cycle disorders
J. Pediatr.
(1999)- et al.
Nitric oxide synthase inhibitors impair reference memory formation in a radial arm maze task in rats
Neuropharmacology
(1998) - et al.
Behavioral and neurotransmitter changes in the urease-infused rat, a model of congenital hyperammonemia
Pediatr. Res.
(1986)
Animal models of congenital hyperammonemia
The sparse fur mouse as a model for gene therapy in ornithine carbamoyltransferase deficiency
Gene Ther.
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