Touchscreen Learning in the Shank3B Mutant Mouse Model of Phelan-Mcdermid Syndrome and Autism Spectrum Disorder

Friday, May 13, 2016: 11:30 AM-1:30 PM
Hall A (Baltimore Convention Center)
N. A. Copping, G. M. Foley, E. L. Berg, B. L. Onaga, J. L. Silverman and M. Yang, Psychiatry and Behavioral Sciences, MIND Institute, Sacramento, CA
Background:   Translocation and breakpoint mutations in SHANK3 have been implicated in autism spectrum disorder (ASD), Phelan-McDermid Syndrome (PMS) and intellectual disabilities (Betancur & Buxbaum, 2013; Gauthier et al., 2009; Leblond etal., 2014; Moessner et al., 2007), leading to the hypothesis  that reduced SHANK3 expression may impair  basic brain functions that are important for social communication and cognition (Durand et al., 2007). Shank3 is a synaptic scaffolding protein, localized in the postsynaptic density.  Mutant mouse and rat models have been generated to evaluate the biological and behavioral consequences of Shank3 gene mutations (Bozdagi et al., 2010; Peca et al., 2011; Bangash et al., 2011; Wang et al., 2011; Kouser et al., 2013). 

Objectives:  The present experiments were designed to evaluate cognitive phenotypes in Shank3B mice. The touchscreen pairwise discrimination task was chosen by virtue of its: (a) conceptual and technical similarities to the CANTAB test battery used for testing cognitive functions in humans, (b) minimal demand on motor abilities, and (c)  translational validity for future clinical trial outcome measures (Silverman et al., 2013).  

Methods:   Breeding pairs were purchased from The Jackson Laboratory (JAX catalogue #017688).  Mice were bred in a conventional mouse vivarium at the University of California Davis School of Medicine in Sacramento.  Pairwise visual discrimination was tested in the automated Bussey-Saksida touchscreen  system for mice (Campden Instruments Ltd/Lafayette Instruments, Lafayette, IL, USA), using a procedure slightly modified from the methods described previously (Brigman & Rothblat, 2008; Bussey et al., 2012; Brigman et al., 2013; Silverman et al. 2013). Mice were trained to discriminate two novel images (spider and plane) displayed side-by-side in two windows on the screen in a spatially pseudo-randomized manner. To examine simple learning under a stringent definition, acquisition was assessed with a performance criterion of  >80%  correct responses (excluding correction trials) over two consecutive sessions and with a minimum of 30 trials completed. Days to reach criterion, number of total trials, number of incorrect responses, and number of correction trials were compared between genotypes.

Results:   As compared to Shank3 wildtype (+/+), Shank3 heterozygous mutant (+/-) mice exhibited impaired learning in the visual discrimination of luminescent-balanced stimuli.  Wildtype controls displayed normal learning typical of the C57BL/6J background strain on all measures. Shank3 +/- mice required more training days to reach criterion and exhibited trends toward making more errors.  Both genotypes reached criterion within the 30-day cutoff.

Conclusions:    We detected a significant deficit in higher-order cognitive functions in the Shank3B mutant mouse model of PMS and ASD, suggesting that this mouse model is a useful preclinical tool for studying neurobiological mechanisms behind cognitive impairments in PMS and ASD. The current findings are the starting point of our future research in which we will investigate multiple domains of cognition and explore pharmacological interventions.

See more of: Animal Models
See more of: Animal Models