Touchscreen learning deficits and normal social approach behavior in the Shank3B model of Phelan–McDermid Syndrome and autism

Abstract

SHANK3 is a synaptic scaffolding protein localized in the postsynaptic density and has a crucial role in synaptogenesis and neural physiology. Deletions and point mutations in SHANK3 cause Phelan–McDermid Syndrome (PMS), and have also been implicated in autism spectrum disorder (ASD) and intellectual disabilities, leading to the hypothesis that reduced SHANK3 expression impairs basic brain functions that are important for social communication and cognition. Several mouse models of Shank3 deletions have been generated, varying in the specific domain deleted. Here we report impairments in cognitive function in mice heterozygous for exon 13–16 (coding for the PDZ domain) deletion. The touchscreen pairwise discrimination task was chosen by virtue of its: (a) conceptual and technical similarities to the Cambridge Neuropsychological Test Automated Battery (CANTAB) and NIH Toolbox Cognition Battery used for testing cognitive functions in humans, (b) minimal demand on motor abilities, and (c) capability to measure many aspects of learning and memory and complex cognitive functions, including cognitive flexibility. The similarity between our mouse tasks and human cognitive assays means a high translational validity in future intervention studies using preclinical models. Our study revealed that Shank3B heterozygous mice (+/–) were slower to reach criterion in the pairwise visual discrimination task, and exhibited trends toward making more errors (first trial errors) and more correction errors than wildtype mice (+/+). Open field activity was normal in +/–, ruling out hypo- or hyperactivity as potential confounds in the touchscreen test. Sociability in the three chamber test was also normal in both +/+ and +/–. These results indicate a deficit in discrimination learning in the Shank3B 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 for our future research in which we will investigate multiple domains of cognition and explore pharmacological interventions.

Touch-screen visual reversal learning is mediated by value encoding and signal propagation in the orbitofrontal cortex

“…Touch-screen automated paradigms have become increasingly utilized to screen rodent models of numerous neuropsychiatric disorders (Marquardt et al, 2014, Yang et al, 2015, Copping et al, 2016, Leach et al, 2016) as these paradigms closely model tools used in the clinical assessment and may increase translational potential of preclinical studies (Mar et al, 2013, Talpos and Steckler, 2013, Hvoslef-Eide et al, 2016). While previous studies have demonstrated that lesion and/or inactivation of the region is sufficient to disrupt visual touch-screen reversal, it has not yet been demonstrated that the rodent OFC mediates reversal of complex visual stimuli in an analogous manner to those seen in primates using visual stimuli (Clarke et al, 2008), or to more species-specific stimuli such as spatial, olfactory or tactile stimuli in rodents (Hamilton and Brigman, 2015b).…”

Shank3B mutant mice display pitch discrimination enhancements and learning deficits

“…There were also no differences found on reversal learning (Peça et al, 2011). However, another study showed Shank3 B HTs were slower to reach criterion on a more difficult pairwise visual discrimination task (Copping et al, 2017). Here, subjects were tested on a complex 4/8 radial arm water maze and Shank3B KOs displayed robust deficits in reference memory.…”

Developmental social communication deficits in the Shank3 rat model of phelan‐mcdermid syndrome and autism spectrum disorder

“…Cohort 1 were offspring of Shank3 1/2 3 Shank3 1/2 breeding pairs, sampled from 9 litters, and tested in open field locomotion at PND 38-40 to confirm typical motor abilities. Pronounced locomotor deficits have been reported in Shank3 mouse models [Peca et al, 2011;Kouser et al, 2013;Speed et al, 2015;Jaramillo et al, 2016;Mei et al, 2016;Copping et al, 2017a;Dhamne et al, 2017] and thus it was crucial that the social communication outcomes of this study not be confounded by motor deficiencies. Cohort 2 were offspring of Shank3 1/2 3 Shank3 1/2 breeding pairs, sampled from 16 litters, and tested in acoustic playback of prosocial species-specific 50-kHz USV at PND 26-33.…”