Article

Stanley, J.L. et al. The mouse beam walking assay offers improved sensitivity over the mouse rotarod in determining motor coordination deficits induced by benzodiazepines. J. Psychopharmacol. 19, 221-227

Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Terlings Park, Harlow, UK.
Journal of Psychopharmacology (Impact Factor: 3.59). 06/2005; 19(3):221-7. DOI: 10.1177/0269881105051524
Source: PubMed

ABSTRACT

The mouse rotarod test of motor coordination/sedation is commonly used to predict clinical sedation caused by novel drugs. However, past experience suggests that it lacks the desired degree of sensitivity to be predictive of effects in humans. For example, the benzodiazepine, bretazenil, showed little impairment of mouse rotarod performance, but marked sedation in humans. The aim of the present study was to assess whether the mouse beam walking assay demonstrates: (i) an increased sensitivity over the rotarod and (ii) an increased ability to predict clinically sedative doses of benzodiazepines. The study compared the effects of the full benzodiazepine agonists, diazepam and lorazepam, and the partial agonist, bretazenil, on the mouse rotarod and beam walking assays. Diazepam and lorazepam significantly impaired rotarod performance, although relatively high GABA-A receptor occupancy was required (72% and 93%, respectively), whereas beam walking performance was significantly affected at approximately 30% receptor occupancy. Bretazenil produced significant deficits at 90% and 53% receptor occupancy on the rotarod and beam walking assays, respectively. The results suggest that the mouse beam walking assay is a more sensitive tool for determining benzodiazepine-induced motor coordination deficits than the rotarod. Furthermore, the GABA-A receptor occupancy values at which significant deficits were determined in the beam walking assay are comparable with those observed in clinical positron emission tomography studies using sedative doses of benzodiazepines. These data suggest that the beam walking assay may be able to more accurately predict the clinically sedative doses of novel benzodiazepine-like drugs.

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    • "The timeline of the tests and ages of animals when tested were: balance beam at 20-22 and repeated at 32-34 weeks, object placement at 20-22 weeks, and open field at 32-34. Motor coordination was evaluated by counting the number of slips made while crossing a round 16 mm balance beam (120 cm long) (Stanley et al., 2005). Prior to each testing session, mice were pre-trained to walk over a 6 cm wide flat wooden plank to diminish anxiety. "
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    ABSTRACT: Christianson syndrome (CS) is an X-linked neurodevelopmental/neurological disorder characterized in males by the following core symptoms that include nonverbal status, intellectual disability, epilepsy, truncal ataxia, postnatal microcephaly and hyperkinesis. CS is caused by mutations in the SLC9A6 gene which encodes a multi-pass transmembrane sodium (potassium)-hydrogen exchanger 6 (NHE6) protein, functional in early recycling endosomes. The extent and variability of the CS phenotype in female heterozygotes, who presumably express the wild-type and mutant SLC9A6 alleles mosaically as a result of X-chromosome inactivation (XCI), have not yet been systematically characterized. Slc9a6 knockout mice (Slc9a6KO) were generated by insertion of the bacterial LacZ/β-galactosidase (bGal) reporter into exon 6 of the X-linked gene. Mutant Slc9a6KO male mice have been shown to develop late endosomal/lysosomal dysfunction associated with glycolipid accumulation in selected neuronal populations as well as patterned degeneration of Purkinje cells (PCs). In heterozygous female Slc9a6KO mice, bGal serves as a transcriptional/XCI reporter and thus facilitates testing of effects of mosaic expression of the mutant allele on penetrance of the abnormal phenotype. Utilizing bGal, we demonstrate mosaic expression of the mutant Slc9a6 allele as well as the mosaically distributed lysosomal glycolipid accumulation and PC pathology in the brains of heterozygous Slc9a6KO female mice. At the behavioral level, we show that heterozygous female mice suffer from visuospatial memory and motor coordination deficits similar to, but less severe than those observed in X-chromosome hemizygous mutant males. Our studies in heterozygous Slc9a6KO female mice provide important clues for understanding the likely phenotypic range of Christianson syndrome among females heterozygous for SLC9A6 mutations and may improve diagnostic practice and genetic counseling by helping to characterize this presumably underappreciated patient/carrier group.
    Preview · Article · Oct 2015 · Disease Models and Mechanisms
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    • "Because of the vast range of situations in which such trade-offs are likely to constrain performance, we wanted to develop a model that could easily be modified to suit different systems or scenarios. Obviously, the model applies to studies of animals walking or running on beams (Losos and Sinervo 1989; Goldstein and Davis 1990; Llewellyn et al. 1990; Sinervo and Losos 1991; Losos and Irschick 1996; Speers et al. 1998; Buddeberg et al. 2004; Stanley et al. 2005; Vanhooydonck et al. 2006), but the model is not limited to these situations. Width of the beam can be set as constant for studies that do not vary the width of the substrate; similarly, the runway need not be a beam. "
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    ABSTRACT: How fast should animals move when trying to survive? Although many studies have examined how fast animals can move, the fastest speed is not always best. For example, an individual escaping from a predator must run fast enough to escape, but not so fast that it slips and falls. To explore this idea, we developed a simple mathematical model that predicts the optimal speed for an individual running from a predator along a straight beam. A beam was used as a proxy for straight-line running with severe consequences for missteps. We assumed that success, defined as reaching the end of the beam, had two broad requirements: (1) running fast enough to escape a predator, and (2) minimizing the probability of making a mistake that would compromise speed. Our model can be tailored to different systems by revising the predator's maximal speed, the prey's stride length and motor coordination, and the dimensions of the beam. Our model predicts that animals should run slower when the beam is narrower or when coordination is worse. © The Author 2015. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology. All rights reserved. For permissions please email: journals.permissions@oup.com.
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    • "However, constant testing environments such as testing within the animal's cage are necessary in order to retrieve reliable and valid data in the adhesive removal test (Schallert and Woodlee, 2005), as should be the case for any other behavioral test as well. Similar findings were found regarding the balance beam test, which was more sensitive in assessment of motor coordination deficits than the rota rod test, albeit these tests were performed in a non-stroke model (Stanley et al., 2005). On the contrary, the pole test cannot be recommended for conditions of severe stroke since some animals are not able to perform the test at all due to the strenuous nature of the task, as has been discussed afore regarding the tight rope test. "
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