Sex‐dependent influence of postweaning environmental enrichment in Angelman syndrome model mice

INTRODUCTION: Angelman syndrome (AS) is a rare neurodevelopmental disorder caused by mutation or loss of UBE3A and marked by intellectual disability, ataxia, autism‐like symptoms, and other atypical behaviors. One route to treatment may lie in the role that environment plays early in postnatal life. Environmental enrichment (EE) is one manipulation that has shown therapeutic potential in preclinical models of many brain disorders, including neurodevelopmental disorders. Here, we examined whether postweaning EE can rescue behavioral phenotypes in Ube3a maternal deletion mice (AS mice), and whether any improvements are sex‐dependent. METHODS: Male and female mice (C57BL/6J Ube3a(tm1Alb) mice and wild‐type (WT) littermates; ≥10 mice/group) were randomly assigned to standard housing (SH) or EE at weaning. EE had a larger footprint, a running wheel, and a variety of toys that promoted foraging, burrowing, and climbing. Following 6 weeks of EE, animals were submitted to a battery of tests that reliably elicit behavioral deficits in AS mice, including rotarod, open field, marble burying, and forced swim; weights were also monitored. RESULTS: In male AS‐EE mice, we found complete restoration of motor coordination, marble burying, and forced swim behavior to the level of WT‐SH mice. We also observed a complete normalization of exploratory distance traveled in the open field, but we found no rescue of vertical behavior or center time. AS‐EE mice also had weights comparable to WT‐SH mice. Intriguingly, in the female AS‐EE mice, we found a failure of EE to rescue the same behavioral deficits relative to female WT‐SH mice. CONCLUSIONS: Environmental enrichment is an effective route to correcting the most penetrant phenotypes in male AS mice but not female AS mice. This finding has important implications for the translatability of early behavioral intervention for AS patients, most importantly the potential dependency of treatment response on sex.