Juvenile Shank3b deficient mice present with behavioral phenotype relevant to autism spectrum disorder

Abstract

Autism spectrum disorder (ASD) is a pervasive, multifactorial neurodevelopmental disorder diagnosed according to deficits in three behavioral domains: communication, social interaction, and stereotyped/repetitive behaviors. Mutations in Shank genes account for ~1% of clinical ASD cases with Shank3 being the most common gene variant. In addition to maintaining synapses and facilitating dendritic maturation, Shank genes encode master scaffolding proteins that build core complexes in the postsynaptic densities of glutamatergic synapses. Male mice with a deletion of the PDZ domain of Shank3 (Shank3B KO) were previously shown to display ASD-like behavioral phenotypes with reported self-injurious repetitive grooming and aberrant social interactions. Our goal was to extend these previous findings and use a comprehensive battery of highly detailed ASD-relevant behavioral assays including an assessment of mouse ultrasonic communication carried out on key developmental days and male and female Shank3B KO mice. We demonstrate that ASD-related behaviors, atypical reciprocal social interaction and indiscriminate repetitive grooming, are apparent in juvenile stages of development of Shank3B KO mice. Our findings underscore the importance of utilizing Shank mutant models to understand the impact of this gene in ASD etiology, which may enable future studies focusing on etiological gene-environment interactions in ASD.

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

“…These activity and social specificities are consistent with the results of previous studies using the same mutant mouse strain (de Chaumont et al, 2019;Vicidomini et al, 2016). Other genetic models of Shank3 mutant mice also display reduced social interest (Shank3-KO ex4-9: (Bozdagi et al, 2010;Wang et al, 2011;Yang et al, 2012); Shank3-KO in ex21: (Duffney et al, 2015); Shank3 ex4-9: (Jaramillo et al, 2016); Shank3-cKI: (Mei et al, 2016); Shank3 exon 4-22 complete KO: (Wang et al, 2016); Shank3B: (Balaan et al, 2019); Shank3 exon 13-16: (Fourie et al, 2018;Peca et al, 2011); Shank3B +/-: (Orefice et al, 2019;Pagani et al, 2019)). Nevertheless, other models failed to detect any atypical social interest in Shank3 mutant mice (Shank3-KO ex4-9: (Drapeau et al, 2014); Shank3-KO ex9: (Lee et al, 2015); Shank3-KO ex 21: (Kouser et al, 2013); Shank3-KO and HZ in ex21: (Speed et al, 2015); Shank3-KO ex11-21 rat model: (Song et al, 2019); conditional Shank3 exon 4-22 knockout in forebrain, striatum, and striatal D1 and D2 cells: (Bey et al, 2018); Shank3 +/Q321R and Shank3 Q321R/Q321R : (Yoo et al, 2019)).…”

“…There are few studies that have investigated ultrasonic communication in Shank3 mutant mice. Pup isolation calls were not affected in Shank3-KO ex4-9 mice (Jaramillo et al, 2016;Yang et al, 2012), the Shank3-KO ex11-21 rat model (Song et al, 2019), or Shank3b-KO mice (Balaan et al, 2019), whereas those of complete Shank3-KO ex4-22 mice showed a lower rate, as well as shorter duration, lower frequency, and lower amplitude (Wang et al, 2016). In the context of a male briefly interacting with an estrus female, the rate of USV emission was not affected in Shank3-KO ex21 (Kouser et al, 2013) or Shank3-KO ex4-9 mice (Yang et al, 2012).…”

A DLG2 deficiency in mice leads to reduced sociability and increased repetitive behavior accompanied by aberrant synaptic transmission in the dorsal striatum

“…However, we found mild decreases in the sociability of these mutant mice, as measured by both three-chamber and direct social interaction tests, whereas Winkler and colleagues [19] reported that Dlg2 ΔE9/ΔE9 mice exhibit hypersociability, as measured by the direct interaction test. While it is conceivable that deletion of different exons generates mixed results in sociability, as has been found among different Shank3 models of ASD [63,64], differences in testing conditions for direct social interactions might contribute to the discrepancy. For instance, the strangers used in the present study were naïve wildtype mice of a different strain, 129/SvJae, whereas the aforementioned study used mice of the same strain and genotype as stranger mice [19].…”

Enhanced Glutamatergic Currents at Birth in Shank3 KO Mice

“…Interestingly, amygdala inputs projecting towards the ventral hippocampus can modulate social behaviors [62], while the activation of the relaxin-3 receptor in the ventral hippocampus results in increased anxiety behaviors and social avoidance [63]. Thus, alterations in anxiety and social interaction behaviors reported in studies using Shank3 −/− mice [45, 64, 65] might be due in part to an impairment in hippocampal activity, and evaluating developmental alterations during the first weeks of life in this structure could shed some light into the underlying mechanisms of this phenotype.…”