The retinal degeneration (rd) gene seriously impairs spatial cognitive performance in normal and Alzheimer’s transgenic mice M. F. Garcia, M. N. Gordon, 1 M. Hutton, 2 J. Lewis, 2 E. McGowan, 2 C. A. Dickey, 1 D. Morgan 1 and G. W. Arendash CA Memory and Aging Research Laboratory, SCA110 and 1 Department of Pharmacology and Experimental Therapeutics; University of South Florida, Tampa, FL 33620; 2 Mayo Clinic Jacksonville, Jacksonville, FL 32224, USA CA Corresponding Author: arendash@chuma.cas.usf.edu Received 7 August 2003; accepted 29 September 2003 DOI: 10.1097/01.wnr.0000101308.86087.21 To determine the e¡ects of the recessive retinal degeneration (rd) gene on behavioral performance, three Alzheimer’s transgenic lines (APPsw, P30lL, APPsw + P301L) and non-transgenic litter- mates were evaluated in a comprehensive behavioral battery be- tween 5 and 8.5 months of age. For all four genotypes collectively, rd homozygosity resulted in profound impairment in spatial cogni- tive tasks requiring visual acuity (Morris maze, platform recogni- tion, and radial arm water maze). Non-transgenic and P301L mutant tau mice contributed most to this rd e¡ect since heterozy- gous and wild type mice performed well. By contrast, spatial cognitive performance of both APPsw-expressing lines was often impaired, irrespective of rd status. Sensorimotor performance was una¡ected by rd homozygosity, while rd e¡ects on anxiety were genotype-dependent (less anxiety in NT, APPsw; more anxiety in P301L, APPsw + P301L). Our results strongly encourage rd screening of genetically manipulated mouse lines produced from rd-carrying strain backgrounds to avoid serious potential confounds in the interpretation of spatially based cognitive performance. NeuroReport 15:73^77  c 2004 Lippincott Williams & Wilkins. Key words: Anxiety level; APP transgenics; Cognitive performance; rd gene; Retinal degeneration; Sensorimotor function; Tau transgenics INTRODUCTION Degeneration of retinal photoreceptors, leading to near complete blindness, is fairly common among rodent strains used in biomedical research. This retinal degeneration is often caused by an autosomal recessive defect in the b- subunit of the rod-specific cGMP-PDE gene. The defect blocks the phototransduction cascade, thus causing in- creased cGMP levels and ensuing induction of Ca 2+ channels to remain open [1]. The rd mutation, if homo- zygous (rd/rd), leads to rapid degeneration of rods within 3 weeks of birth, followed by degeneration of cones thereafter [2]. While the mechanism responsible for this retinal degeneration is not fully understood, it is thought to involve apoptotic cell death [3]. The rd mutation has minimal effects on retinal ganglion cells and does not appear to affect any other CNS neuronal populations. Of 65 inbred mouse strains investigated, 20% were found to carry the rd gene [4]; indeed, the rd mutation is fixed in C3H, CBA, and FVB strains [5]. Given the prominent use of several rd-carrying mouse strains to generate transgenic/ knockout models for various neurological diseases, it is important to determine the behavioral consequences of rd homozygosity. Such consequences, left undetected, could seriously confound interpretation of behavioral data col- lected from genetically manipulated mouse models. In this context, surprisingly few studies have attempted to deter- mine the extent to which retinal degeneration affects behavioral performance. In view of the considerable spontaneous retinal degeneration that occurs during aging in albino rats, Spencer et al. [6] found that impairment in Morris maze spatial learning of aged Sprague–Dawley rats is significantly correlated with degree of retinal degenera- tion [6]. In another study, C3H and CBA mice homozygous for rd were impaired in a one-way active avoidance paradyme requiring animals to run through a small hole to avoid footshock [7]. By contrast, rd/rd mice tested in a water T-maze task not requiring visual acuity were not significantly impaired in their ability to locate an escape ladder [8]. Effects of the rd mutation on anxiety are unresolved, with one study reporting less anxiety in the elevated zero-maze for three inbred strains of mice carrying the rd/rd mutation (C3H, CBA, and FVB/NJ) compared to five other inbred strains [9]. Although the aforementioned behavioral studies suggest seriously confounding effects of retinal degeneration on assessment of cognitive/anxiety tasks requiring visual acuity, each of those studies involved only a single behavioral task and none involved genetically manipulated COGNITION NEUROREPORT 0959-4965  c Lippincott Williams & Wilkins Vol 15 No 1 19 January 2004 73 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.