Autistic-Like Behaviors in GAP-43 Deficient Mouse That Displays Disordered Connectivity and Autism-Related Gene Expression

Background: Autism spectrum disorder (ASD) is a complex neurological disorder involving impaired social interactions, communication deficiencies and a tendency toward rigid, repetitive behaviors.  An emerging theory of ASD proposes that disordered connectivity is responsible for the development of autistic behavior. Growth associated protein 43 (GAP-43) is important for normal axon targeting and stabilization of productive axonal contacts. A mouse lacking one copy of the GAP-43 gene (HZ) shows multiple abnormalities in long axonal projections. In addition, neonates show overgrowth of the somatosensory cortex.  Adults recover normal cortical dimensions but display enlarged excitatory receptive fields.  These findings are evidence that the GAP-43 HZ mouse is a model of disordered connectivity.  Importantly, GAP-43 HZ mice also have altered expression of more than 100 genes implicated in ASD, including Fragile X, Reelin, MECP2, UBE3A, GABARB3, Wnt2, Dishevelled 1, and Engrailed 2.  Thus, deletion of a single GAP-43 allele creates an autistic-like gene expression pattern in an environment displaying disordered connectivity.

Objectives: Since GAP-43 HZ mice display disordered connectivity and autistic-like gene expression, our objective was to examine its behavioral phenotype.  We hypothesized that GAP-43 HZ mice would display specific autism-like behavioral deficiencies.

Methods: We tested this hypothesis with behavioral tasks designed to assess face validity in mouse models of autism.  Tests included t-maze, Morris water maze, open-field object recognition, social approach, juvenile interaction, elevated-plus maze, light-dark box, forced swim test, tail suspension test, fear conditioning, and social transmission of food preference.

Results: We found that GAP-43 HZ mice show deficiencies in reversal learning (resistance to change).  We also found gender-specific increases in anxiety and stress-induced behavioral withdrawal, as well as deficiencies in spatial habituation and learning.  To date, we have not found significant deficiencies in social interaction or social communication. 

Conclusions: We conclude that disordered connectivity and autism-like gene expression in GAP-43 HZ mice may be associated with some, but not all, mouse behaviors that exhibit face validity with symptoms of ASD.