Differentially altered social dominance- and cooperative-like behaviors in Shank2- and Shank3-mutant mice

Abstract

Background Recent progress in genomics has contributed to the identification of a large number of autism spectrum disorder (ASD) risk genes, many of which encode synaptic proteins. Our understanding of ASDs has advanced rapidly, partly owing to the development of numerous animal models. Extensive characterizations using a variety of behavioral batteries that analyze social behaviors have shown that a subset of engineered mice that model mutations in genes encoding Shanks, a family of excitatory postsynaptic scaffolding proteins, exhibit autism-like behaviors. Although these behavioral assays have been useful in identifying deficits in simple social behaviors, alterations in complex social behaviors remain largely untested. Methods Two syndromic ASD mouse models—Shank2 constitutive knockout [KO] mice and Shank3 constitutive KO mice—were examined for alterations in social dominance and social cooperative behaviors using tube tests and automated cooperation tests. Upon naïve and salient behavioral experience, expression levels of c-Fos were analyzed as a proxy for neural activity across diverse brain areas, including the medial prefrontal cortex (mPFC) and a number of subcortical structures. Findings As previously reported, Shank2 KO mice showed deficits in sociability, with intact social recognition memory, whereas Shank3 KO mice displayed no overt phenotypes. Strikingly, the two Shank KO mouse models exhibited diametrically opposed alterations in social dominance and cooperative behaviors. After a specific social behavioral experience, Shank mutant mice exhibited distinct changes in number of c-Fos+ neurons in the number of cortical and subcortical brain regions. Conclusions Our results underscore the heterogeneity of social behavioral alterations in different ASD mouse models and highlight the utility of testing complex social behaviors in validating neurodevelopmental and neuropsychiatric disorder models. In addition, neural activities at distinct brain regions are likely collectively involved in eliciting complex social behaviors, which are differentially altered in ASD mouse models.

MEK inhibition ameliorates social behavior phenotypes in a Spred1 knockout mouse model for RASopathy disorders

“…Notably, the increased social dominance phenotype observed in Spred1-/- mice is highly similar to increased social dominance observed in the tube test in several other mouse models for monogenic forms of ASD, including several different Shank3 mouse models [ 60 , 61 ], Shank2 Δ6−7 mice [ 62 ] and Fmr1 y/- mice [ 40 ]. Increased winning in the tube may model an inability to recognize the social status of conspecifics.…”

Comparison of SHANK3 deficiency in animal models: phenotypes, treatment strategies, and translational implications

“…Cre-expression, and thus deletion of Shank3 in neocortical excitatory neurons (ex4-22|ALL-NEX Cre ), Dlx5/6 -positive GABAergic forebrain neurons (ex4-22|ALL-Dlx5/6 Cre ), which include various subclasses of neocortical interneurons but also MSNs as principal striatal projection neurons [ 169 – 174 ], DRD1- (ex4-22|ALL-Drd1 Cre ) and DRD2-positive neurons (ex4-22|ALL-Drd2 Cre ) [ 129 ], did not induce the phenotype previously observed in the constitutive KO model [ 128 ], though it has to be noted that such deficits of constitutive KO mice were also not replicated in this study. Mixed evidence and even conflicting results concerning social interaction deficits were observed in the models ex9|ANK [ 82 , 175 ], ex13|PDZ [ 139 , 176 ], ex21|PRO [ 125 , 177 – 179 ], and the rat model ex6|ANK [ 134 , 180 ]. Intact social motivation and interaction was described in the analysis of the models ex4-7|ANK [ 90 ], ex8|ANK-Q321R [ 132 ], ex21|PRO-InsG3728 [ 126 ], and ex11-21|SH3-PRO in rats [ 135 ].…”

“…Mixed evidence concerning the ability to recognize familiar conspecifics was observed in the model ex13-16|PDZ [ 90 , 155 , 161 , 164 , 166 , 168 ], where some studies found aberrant social recognition, while it seemed to be intact in others. No deficits of social recognition were found in the murine models ex4-9|ANK [ 78 , 80 , 167 ], ex9|ANK [ 82 , 175 ], ex14-16|PDZ [ 131 ], and ex21|PRO-InsG3728 [ 126 ]. Similarly, specific deletion of SHANK3 in dorsal telencephalic excitatory neurons and glia (ex14-16|PDZ-Emx1 Cre ) [ 133 ], or GABAergic neurons (ex14-16|PDZ-Viaat Cre ) [ 131 ] did not cause dysfunctional social recognition.…”

A water-reward task assay for evaluating mouse mutualistic cooperative behavior

“…However, using house mice as subjects allows easier molecular-genetic manipulations and convenient coupling to other established behavior assays. In a recent study, Kyung et al used Shank2 KO and Shank3 KO mice to model autism spectrum disorder; they evidenced increased and decreased cooperative behaviors in Shank2 KO and Shank3 KO mice, respectively, which additionally correlated well with altered social dominance behaviors 14 .…”

“…Comparing the performance between mice and rats in this assay, we found the efficacy (defined as the number of rewards divided by activity) in mice was only about half that in rats, which further reduced to¼ considering the mouse box is also half-long. Futhermore, the latency (defined as time to receive the first reward) in mice is one order of magnitude higher 14,15 . The low efficacy and high latency in mice make the assay insensitive for detecting subtle behavioral alterations.…”