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

Abstract

AutDB features a modular framework that aims at collating multifactorial risk factors associated with autism spectrum disorder (ASD). The animal model (AM) module of AutDB was first developed for mouse models of genes and CNVs associated with ASD (Kumar et al., 2011).Subsequently, environmentally induced rodent models were introduced to capture the full spectrum of risk-factors associated with ASD, along with idiopathic models represented by inbred strains. Using the data systematically annotated in AutDB, we depict the intricate trends in the research findings based on rodent models of ASD. We identify the top 30 most frequently studied phenotypes extracted from 911 genetic, 269 induced and 17 inbred rodent models of ASD extracted from 787 publications. As expected, many of these include animal model equivalents of the 'core' phenotypes associated with ASD, as well as several comorbid features of ASD including anxiety, seizures and motor-control deficits. Uniquely, AutDB curates rescue models where various treatment strategies were used in rodent ASD models to alleviate ASDrelevant phenotypes. We further examine ASD models based on 52 genes and 2 CNV loci to identify 24 pharmaceutical agents that were used in 2 or more paradigms for testing their efficacy. As a case study, we analyze various Shank3 mouse models providing a highresolution view of the in vivo role of this high-confidence ASD gene. Together, this resource provides a snapshot of genetic and induced models of ASD within a shared annotation platform to examine the complex meshing of diverse ASD-associated risk-factors.ASD, annotated using a shared and standardized framework. Another distinctive and unique feature of the AutDB resource is the inclusion of rescue models, in which drugs and procedural, genetic or dietary manipulations are used in rodent ASD models in an attempt to rescue ASDrelevant phenotypes. Together, AutDB represents a comprehensive resource including genetic and nongenetic animal models relevant in ASD biology.Using data curated in the AM module over the past 8 years we demonstrate characteristic patterns in analyses undertaken to study genetic and environmentally induced rodent models of ASD. Analysis of trends based on rodent model findings shows that the most frequently assessed phenotypes are related to core features of human ASD such as social interactions, ultrasonic vocalization and repetitive behavior. Additionally, neuroanatomical features like changes in dendritic architecture, observed in post-mortem human studies of ASD brains (Martinez-Cerdeno, 2017), are also frequently examined in rodent models along with electrophysiology conducted on acute brain slices. With a view to facilitating translational research, we highlight pharmaceutical drugs administered to several ASD models. Finally, as a case study, we present a comprehensive analysis of phenotypes studied in rodent models of Shank3, one of the leading genetic risk factors of ASD. Competing interests