Development of sex- and genotype-specific behavioral phenotypes in a Shank3 mouse model for neurodevelopmental disorders

Abstract

Individuals with a SHANK3-related neurodevelopmental disorder, also termed Phelan-McDermid syndrome or abbreviated as PMS, exhibit significant global developmental delay, language impairment, and muscular hypotonia. Also common are repetitive behaviors and altered social interactions, in line with a diagnosis of autism spectrum disorders. This study investigated the developmental aspect of autism-related behaviors and other phenotypes in a Shank3-transgenic mouse model. The animals underwent two sets of identical behavioral experiments, spanning motor skills, social and repetitive behavior, and cognition: baseline began at 5 weeks of age, corresponding to human adolescence, and the follow-up was initiated when aged 13 weeks, resembling early adulthood in humans. Interestingly, the animals displayed relatively stable phenotypes. Moreover, motor coordination and endurance were impaired, while muscle strength was unchanged. Surprisingly, the animals displayed only minor impairments in social behavior, but pronounced stereotypic and repetitive behaviors. Some behavioral tests indicated increased avoidance and anxiety. While spatial learning and memory were unchanged, knockout animals displayed slightly impaired cognitive flexibility. Female animals had similar abnormalities as males in the paradigms testing avoidance, anxiety, and cognition, but were less pathological in motor function and repetitive behavior. In all test paradigms, heterozygous Shank3 knockout animals had either no abnormal or a milder phenotype. Accurate characterization of animal models for genetic diseases is a prerequisite for understanding the pathophysiology. This is subsequently the basis for finding suitable and, ideally, translational biomarkers for therapeutic approaches and, thereby reducing the number of animals needed for preclinical trials.

Endothelial SHANK3 Controls Tight Junction of Neonatal Blood-Brain Barrier

“…Intriguingly, this effect was particularly notable in male neonates (Fig. 1g), consistent with existing literature indicating a higher prevalence of ASD in males compared to females, as observed in both human patients and animal models [19][20][21] .…”

“…We unexpectedly but constantly observed male-predominant phenotypes in eShank3-KO mice, including abnormal TJ structure, increased neonatal BBB permeability, impaired neuronal excitability, and autisticlike behaviors. Although sex differences have been reported in ASD human patients and animal models [19][20][21] , the underlying mechanisms remain undetermined. Further comprehensive studies using the BBBoriented model system could contribute to elucidating the mechanisms of why the female is more protected from the genetic risk of ASD.…”

Psilocybin induces acute anxiety and changes in amygdalar phosphopeptides independently from the 5-HT2A receptor

“…However, several studies have suggested this test does not determine anxiety behaviors, but rather repetitive or perseverative behaviors, 38 and some mouse models with anxiety display decreased marbles buried. 39

Figure 1 The effect of psilocybin on anxiety-related behavioral tests (A) Schematic representation of experimental design, created with BioRender.com . (B) Time spent in center of open field.

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Shank3 related muscular hypotonia is accompanied by increased intracellular calcium concentrations and ion channel dysregulation in striated muscle tissue

“…SHANK3 deficiency is known to be associated with muscular deficits ( Zhou et al, 2019 ; Lutz et al, 2020 ; Bauer et al, 2023 ). However, the pathways by which a Shank3 deletion causes these effects and whether they result in hypotonia remain unknown.…”

“…Despite this reduction, certain SHANK3 isoforms continue to be expressed ( Lutz et al, 2020 and Lutz et al, 2022 ). Based on Bauer et al, 2023 , where heterozygous and homozygous animals have been analyzed, this current study used Shank3Δ11(−/−). Using human muscle sections has limitations due to the small sample size of three patients, per age group one biopsy per individual, and the fact that they are separate individuals with genetic differences.…”