Get access

Autism-Related Neuroligin-3 Mutation Alters Social Behavior and Spatial Learning

Authors

  • Thomas C. Jaramillo,

    1. Department of Neurology & Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas, Texas
    Search for more papers by this author
  • Shunan Liu,

    1. Department of Neurology & Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas, Texas
    Search for more papers by this author
  • Ami Pettersen,

    1. Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas
    Search for more papers by this author
  • Shari G. Birnbaum,

    1. Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas
    Search for more papers by this author
  • Craig M. Powell

    Corresponding author
    1. Department of Neurology & Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas, Texas
    2. Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas
    3. Neuroscience Graduate Program, The University of Texas Southwestern Medical Center, Dallas, Texas
    • Address for correspondence and reprints: Craig M. Powell, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8813. E-mail: craig.powell@utsouthwestern.edu

    Search for more papers by this author

Abstract

Multiple candidate genes have been identified for autism spectrum disorders. While some of these genes reach genome-wide significance, others, such as the R451C point mutation in the synaptic cell adhesion molecule neuroligin-3, appear to be rare. Interestingly, two brothers with the same R451C point mutation in neuroligin-3 present clinically on seemingly disparate sides of the autism spectrum. These clinical findings suggest genetic background may play a role in modifying the penetrance of a particular autism-associated mutation. Animal models may contribute additional support for such mutations as functionally relevant and can provide mechanistic insights. Previously, in collaboration with the Südhof laboratory, we reported that mice with an R451C substitution in neuroligin-3 displayed social deficits and enhanced spatial learning. While some of these behavioral abnormalities have since been replicated independently in the Südhof laboratory, observations from the Crawley laboratory failed to replicate these findings in a similar neuroligin-3 mutant mouse model and suggested that genetic background may contribute to variation in observations across laboratories. Therefore, we sought to replicate our findings in the neuroligin-3 R451C point mutant knock-in mouse model (NL3R451C) in a different genetic background. We backcrossed our NL3R451C mouse line onto a 129S2/SvPasCrl genetic background and repeated a subset of our previous behavioral testing. NL3R451C mice on a 129S2/SvPasCrl displayed social deficits, enhanced spatial learning, and increased locomotor activity. These data extend our previous findings that NL3R451C mice exhibit autism-relevant behavioral abnormalities and further suggest that different genetic backgrounds can modify this behavioral phenotype through epistatic genetic interactions. Autism Res 2014, 7: 264–272. © 2014 International Society for Autism Research, Wiley Periodicals, Inc.

Get access to the full text of this article

Ancillary