Mouse Model Systems of Autism Spectrum Disorder: Replicability and Informatics Signature

Abstract

Background: Phenotyping mouse model systems of human disease has proven to be a difficult task, with frequent poor inter-and intra-laboratory replicability and translatability, particularly in behavioral domains such as social and verbal function. However, establishing robust animal model systems with strong construct validity is of fundamental importance as they are central tools for understanding disease pathophysiology and developing therapeutics. To complete our studies of mouse model systems relevant to autism spectrum disorder (ASD), we present a replication of the main findings from our two published studies comprising five genetic mouse model systems of ASD.Methods: To assess the robustness of our previous results, we chose the two model systems that showed the greatest phenotypic differences, the Shank3/F and Cntnap2, and repeated assessments of general health, activity, and social behavior. We additionally explored all five model systems in the same framework, comparing all results obtained in this three-yearlong effort using informatics techniques to look for commonalities and differences.Results: Results in the current study were very similar to our previously published results. The informatics signatures of the two model systems chosen for the replication showed that they were most distinguished by activity levels. Although the two model systems were opposite in this regard, those aspects of their social behavior not confounded by activity (vocalizations) were similar. P a g e | 2Conclusions: Our results showed high intra-laboratory replicability of results, even for those with effect sizes that were not particularly large, suggesting that discrepancies in the literature may be dependent on subtle differences in testing conditions, housing enrichment, or background strains and not so much on the variability of the behavioral phenotypes. The overall informatics analysis suggests two main classes of model systems that in some aspects lie on opposite ends of the behavioral spectrum, supporting the view that autism is not a unitary concept.4.

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

“…Increased self grooming and other repetitive behaviors have been consistently reported in the models ex4-22|ALL [ 128 – 130 ], ex11|SH3 [ 123 ], ex13|PDZ [ 139 , 176 ], ex13-16|PDZ [ 83 , 90 , 155 , 159 , 160 , 162 – 164 , 166 , 168 , 181 – 183 ], ex14-16|PDZ [ 131 ], ex21|PRO [ 125 , 178 , 179 ], and ex11-21|SH3-PRO in rats [ 135 ]. Interestingly, in murine models ex21|PRO-InsG3680 [ 127 ] and ex8|ANK-Q321R [ 132 ], which mimick ASD-associated mutations, increased repetitive behavior was observed, whereas this was not the case in ex21|PRO-R1117X [ 127 ] mice, which harbor a schizophrenia-associated mutation.…”

“…Abnormalities concerning social communication behaviors were consistently observed in mice of the models ex4-22|ALL [ 128 , 129 ], ex4-9|ANK [ 78 , 80 , 124 , 155 ], ex13-16|PDZ [ 155 , 158 , 159 , 163 ], ex14-16|PDZ [ 131 ], and ex17|PRM-S685I [ 94 ], although single studies did not observe differences compared to wildtype animals [ 130 , 162 ]. Findings were not consistent in two studies focusing on the rat model ex6|ANK [ 134 , 180 ].…”

“…High levels of anxiety were reported in models with the deletions ex4-22|ALL [ 128 – 130 ], ex13-16|PDZ [ 83 , 90 , 155 , 159 , 160 , 163 , 164 , 168 , 183 , 188 , 189 ], ex11-21|SH3-PRO in rats [ 135 ], and in mice with schizophrenia- or ASD-associated mutations (ex21|PRO-R1117X, -InsG3680 [ 127 ] or -InsG3728 [ 126 ]), while only slight differences were observed in the models ex13|PDZ [ 139 , 176 ] and ex14-16|PDZ [ 131 ]. Elevated anxiety levels were also replicated in conditional KO-strategies, inducing SHANK3 deficiency in somatosensory neurons or cells derived from the caudal embryo (ex13-16|PDZ-Advillin Cre or -Cdx2 Cre [ 140 ]), but also in GABAergic (ex14-16|PDZ-Viaat Cre [ 131 ]) or DRD1-positive neurons (ex4-22|ALL-Drd1 Cre [ 129 ]).…”

“…Sensorimotor function is often assessed in tasks such as the rotarod, which primarily targets coordination, by motor reflexes induced through sensory stimuli such as the righting reflex and geotaxis, and by gait analysis. Abnormalities concerning tasks depending on sensorimotor function have been described in SHANK3-deficient rodents of the deletion models ex4-22|ALL [ 128 , 130 ], ex4-9|ANK [ 78 , 124 , 155 , 167 ], ex11|SH3 [ 123 ], and ex13-16|PDZ [ 83 , 155 , 159 , 183 ], or mice harboring schizophrenia- and ASD-associated mutations (ex21|PRO-R1117X, -InsG3680 [ 127 ] or -InsG3728 [ 126 , 187 ]). Notably, single studies did not observe differences between wildtype and mutant mice of some of these strains [ 80 , 90 , 166 ].…”

Mouse model systems of autism spectrum disorder: Replicability and informatics signature

“…In addition to the NC3Rs ARRIVE Guidelines Checklist, the data that support the findings of this study are openly available on the Open Science Framework platform at https://osf.io/4mujp/ (DOI: 10.17605/OSF.IO/4MUJP). 26 …”