Shank2 Mutant Mice Display Hyperactivity Insensitive to Methylphenidate and Reduced Flexibility in Social Motivation, but Normal Social Recognition

Abstract

Mouse models of autism can be used to study evolutionarily conserved mechanisms underlying behavioral abnormalities in social communication and repetitive behaviors. SHANK genes code for synaptic scaffolding proteins at excitatory synapses and mutations in all SHANK genes have been associated with autism. Here, we present three behavioral aspects of the mutant mice deleted for exon 16 in Shank2. First, we treated Shank2 mutant mice with methylphenidate to rescue the hyperactivity. Our failure to do so suggests that the hyperactivity displayed by Shank2 mutant mice is not related to the one displayed by the typical mouse models of hyperactivity, and might be more closely related to manic-like behaviors. Second, by testing the effect of group housing and social isolation on social interest, we highlighted that Shank2 mutant mice lack the typical flexibility to modulate social interest, in comparison with wild-type littermates. Finally, we established a new protocol to test for social recognition in a social context. We used this protocol to show that Shank2 mutant mice were able to discriminate familiar and unknown conspecifics in free interactions. Altogether, these studies shed some light on specific aspects of the behavioral defects displayed by the Shank2 mouse model. Such information could be used to orient therapeutic strategies and to design more specific tests to characterize the complex behavior of mouse models of autism.

Learning and reaction times in mouse touchscreen tests are differentially impacted by mutations in genes encoding postsynaptic interacting proteins SYNGAP1, NLGN3, DLGAP1, DLGAP2 and SHANK2

“…Lastly, we found that Shank2 −/− mice were hyperactive during habituation, which is in line with published reports using similar mutants 56‐59 . However, visual discrimination acquisition and reversal learning were not significantly different in Shank2 −/− mice and their WT littermates.…”

Spontaneous social communication in laboratory mice - placing ultrasonic vocalizations in their behavioral context

“…The emission of a large number of spontaneous USVs suggests that female mice are sufficiently aroused in their normal "home-cage-like" life. In short-term experiments, socially-housed mice never reach this level of excitement during the first minutes of interaction and therefore emit few USVs (e.g., (Ey et al, 2018;Hammerschmidt et al, 2012)). The emission of a large quantity of USVs can only be reached by social deprivation over such short periods.…”

“…During development, mouse pups isolated from the dam and littermates emit USVs as distress calls that trigger approach and retrieval by the mother (Sewell, 1970;Zippelius and Schleidt, 1956). In juveniles and adults, socially-deprived mice are highly motivated to interact with conspecifics; this maximizes the quantity of USVs emitted, which may be used to regulate close contacts and hierarchy (Ey et al, 2018;Moles et al, 2007). Finally, an estrous female, or at least its odor, stimulates adult males to vocalize (Chabout et al, 2015;Holy and Guo, 2005).…”

Mice with Mutations in Trpm1, a Gene within the locus of 15q13.3 Microdeletion Syndrome, Display Pronounced Hyperactivity and Decreased Anxiety-Like Behavior.

“…In Ndrg2 de cient mice, their ADHD-like hyperactivity was not rescued by MPH [46]. Shank2 and Fmr1 mutant mice, both are the model of autism, display hyperactivity, but the injection of MPH increased their locomotion activity [47,48]. Relevant to the effect of MPH in Shank2 and Fmr1 de cient mice, hyperactivity in Trpm1 de cient mice may not be related to ADHD, but instead autism which is also one of the phenotypes in 15q13.3 microdeletion syndrome (Table S1) [5,49].…”