The Spatial Learning Phenotype of Heterozygous Leaner Mice is Robust to Systematic Variation of the Housing Environment

Providing stimulation and allowing the performance of motivated behaviors through environmental enrichment improves learning and memory in rodents and delays cognitive impairment in neurodegenerative disease models. The leaner mutation affects the Ca_v2.1 voltage-gated calcium channel α_1A-subunit gene, and homozygous mice show severe phenotypic alterations. Although several authors have described heterozygous mice as normal, recent studies in our laboratory indicate motor and cognitive impairment in tg^la/+ mice. In the present study, we evaluated whether this impairment is robust to systematic variation of the housing environment from barren to standard and furnished (enriched) cages. Wildtype (n = 55) and tg^la/+ (n = 79) C57Bl/6J mice were assigned randomly to 1 of the 3 housing systems and tested on the Morris water maze at 6, 12, and 20 mo of age. The results confirmed impaired performance in tg^la/+ mice, particularly in older mice. At 12 and 20 mo, only wildtype (and not tg^la/+) mice showed evidence of learning (spending increased time in the target quadrant) during the probe trial. Housing also affected performance: at 12 mo, only mice from furnished cages showed evidence of learning, and in aged mice (20 mo), only those housed in more complex environments showed long-term memory (8 mo after previous testing) of the platform position. In conclusion, a heterozygous mutation in a Ca²⁺ channel gene causes cognitive deficits in leaner mice that are robust to environmental variation but attenuated by physical and behavioral stimulation.