Reconsidering animal models used to study autism spectrum disorder: Current state and optimizing future

Abstract

Neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD) and intellectual disability (ID), are pervasive, often lifelong disorders, lacking evidence-based interventions for core symptoms. With no established biological markers, diagnoses are defined by behavioral criteria. Thus, preclinical in vivo animal models of NDDs must be optimally utilized. For this reason, experts in the field of behavioral neuroscience convened a workshop with the goals of reviewing current behavioral studies, reports, and assessments in rodent models. Goals included: (a) identifying the maximal utility and limitations of behavior in animal models with construct validity; (b) providing recommendations for phenotyping animal models; and (c) guidelines on how in vivo models should be used and reported reliably and rigorously while acknowledging their limitations. We concluded by recommending minimal criteria for reporting in manuscripts going forward. The workshop elucidated a consensus of potential solutions to several problems, including revisiting claims made about animal model links to ASD (and related conditions). Specific conclusions included: mice (or other rodent or preclinical models) are models of the neurodevelopmental insult, not specifically any disorder (e.g., ASD); a model that perfectly recapitulates a disorder such as ASD is untenable; and greater attention needs be given to validation of behavioral testing methods, data analysis, and critical interpretation.

Keywords: autism; behavior; developmental; genetic; genetic disorder; intellectual disability; models; mouse models; neurodevelopmental disorder; social; syndrome.

FIGURE 1

Literature review of behavioral phenotyping of the so‐called "autism spectrum disorder (ASD) mouse models" reveals inconsistent patterns in behavior execution and reporting. A literature review of the so‐called "mouse models of ASD" was conducted to observe trends in behavioral phenotyping execution and reporting. We analyzed how often core diagnostic criteria of ASD were assessed in mouse models, how often these criteria were paired with other behavioral domains, and how often common assays used in social and repetitive and restricted behaviors were used as singular outcomes for each domain. We also highlighted how often four key features of experimental design were not clearly reported to highlight gaps in reporting that may inhibit or prohibit successful interpretation and reproduction of data published