A multifaceted approach for analyzing complex phenotypic data in rodent models of autism

Abstract

Autism (MIM 209850) is a multifactorial disorder with a broad clinical presentation. A number of high-confidence ASD risk genes are known; however, the contribution of non-genetic environmental factors towards ASD remains largely uncertain. Here, we present a bioinformatics resource of genetic and induced models of ASD developed using a shared annotation platform. Using this data, we depict the intricate trends in the research approaches to analyze rodent models of ASD. We identify the top 30 most frequently studied phenotypes extracted from rodent models of ASD based on 787 publications. As expected, many of these include animal model equivalents of the “core” phenotypes associated with ASD, such as impairments in social behavior and repetitive behavior, as well as several comorbid features of ASD including anxiety, seizures, and motor-control deficits. These phenotypes have also been studied in models based on a broad range of environmental inducers present in the database, of which gestational exposure to valproic acid (VPA) and maternal immune activation models comprising lipopolysaccharide (LPS) and poly I:C are the most studied. In our unique dataset of rescue models, we identify 24 pharmaceutical agents tested on established models derived from various ASD genes and CNV loci for their efficacy in mitigating symptoms relevant for ASD. As a case study, we analyze a large collection of Shank3 mouse models providing a high-resolution view of the in vivo role of this high-confidence ASD gene, which is the gateway towards understanding and dissecting the heterogeneous phenotypes seen in single-gene models of ASD. The trends described in this study could be useful for researchers to compare ASD models and to establish a complete profile for all relevant animal models in ASD research.Electronic supplementary materialThe online version of this article (10.1186/s13229-019-0263-7) contains supplementary material, which is available to authorized users.

Deletion of BDNF in Pax2 Lineage-Derived Interneuron Precursors in the Hindbrain Hampers the Proportion of Excitation/Inhibition, Learning, and Behavior

“…(vi) Finally, various phenotypic characteristics of Bdnf Pax 2 KO mice are reminiscent of mouse models relevant to neurodevelopmental disorders, such as ASD. These include reduced PV-IN labeling ( Takano, 2015 ; Pirone et al, 2018 ; Goel et al, 2019 ), elevation of Arc levels ( Korb and Finkbeiner, 2011 ; Goel et al, 2019 ), increased fEPSPs ( Mohn et al, 2014 ), as well as elevated corticosterone levels ( Das et al, 2019 ). Also, a mouse line deficient in adenomatous polyposis coli protein, a key regulator of synapse maturation ( Hickman et al, 2015 ), also developed an autistic phenotype ( Mohn et al, 2014 ; Alexander et al, 2020 ).…”

Excessive aggression, ADHD- and ASD-like phenotypes in TPH2- and brain ganglioside-deficient mice

“…Our data showing central and peripheral over-production of IL-1β, IL-6, and TNF are in keeping with these findings, as well as with previous demonstrations of systemic inflammation and up-regulated brain expression of IL-1β, IL-6, IL-17, IL-18, IL-33, TNF and astrocyte/microglia activation in animal models of ASD (Das et al, 2019;Wei et al, 2012Wei et al, , 2016. We also found the upregulation of IL-1β in the double transgenic St3gal5-deficient 5xFAD female mice (Dukhinova et al, 2019).…”

“…The impaired conditioned taste conditioning suggests cognitive rigidity in St3gal5 −/− animals, an important element of ASD-like phenotype (Haratizadeh et al, 2021). The presence of motor deficits in the St3gal5 −/− mice also agrees with other studies in which an association between ASD syndrome and motor dyscoordination has been described (Das et al, 2019;Lewis et al, 2007;Thapar et al, 2017).…”

“…Social behaviours were also abnormally altered by the administration of LPS which is in keeping with findings that LPS exacerbates ASD-like behaviours in other mouse models including BTBR mice, a genetic model of ASD (Das et al, 2019;McFarlane et al, 2008;Onore et al, 2013). The impaired conditioned taste conditioning suggests cognitive rigidity in St3gal5 −/− animals, an important element of ASD-like phenotype (Haratizadeh et al, 2021).…”

“…For example, in mice, abnormal interactions with counter partners, excessive following, dominancy, increased grooming and -196 -rearing, impaired inhibitory learning, are all signs of ASD-like behavior (Das et al, 2019;Lewis et al, 2007;Onore et al, 2013;Tatsukawa et al, 2019). We observed increased following behavior in male mutants, decreased social exploration in female mice, and aberrant nose-anal interaction in both sexes which are suggestive of social dysfunction.…”