Elsevier

Brain Research

Volume 876, Issues 1–2, 8 September 2000, Pages 1-9
Brain Research

Research report
Impaired cognitive performance in ornithine transcarbamylase-deficient mice on arginine-free diet

https://doi.org/10.1016/S0006-8993(00)02589-0Get rights and content

Abstract

Sparse-fur (spf) mice are a model for the congenital deficiency of ornithine transcarbamylase (OTC), the most common inborn error of urea synthesis in man. In this study, performance of clinically stable spf and control mice (8–10-weeks-old) on two learning tests was assessed under normal Arg(+) or arginine-free Arg(−) diet conditions. Used as an indicator of the metabolic status of the animals, plasma ammonia concentrations were significantly higher in spf than in controls on normal diet, and increased even more during the Arg(−) diet episode. Behaviourally, we found no difference in passive avoidance learning between control and spf mice on Arg(+) diet, whereas in spf mice receiving Arg(−) diet during training, retention performance was significantly reduced. In the hidden-platform water maze, spf mice on Arg(+) diet only showed decreased swimming velocity compared to controls. In mice on Arg(−) diet during the first week of acquisition training, performance on acquisition and retention (probe) trials showed that spf mice experienced more difficulties in actually locating the platform. Visible-platform control experiments only showed a reduction in swimming velocity in spf mice on either diet. We conclude that cognitive performance is impaired in spf mice as a consequence of Arg(−) diet-induced neurochemical alterations.

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.

Section snippets

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.

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