The Importance of Translational Research for Neurodevelopmental Disorders and Autism Spectrum Disorders

Translational research is the process of transforming fundamental biological discoveries into safe and efficacious interventions for patients. This specialized field is of particular importance for neurodevelopmental disorders (NDDs), a broad class of behaviorally defined conditions including autism spectrum disorder (ASD), attention deficit/hyperactivity disorder (ADHD), intellectual and developmental disabilities (IDDs), and related disorders. NDDs present unique translational challenges including (i) a lack of biological diagnostic markers; (ii) the fact that they are diagnosed exclusively by behavioral criteria; (iii) their involvement of dysfunction in complex brain circuitry; and (iv) that there is no single unifying biological mechanism. This chapter reviews the current landscape of translational neuroscience for NDDs, examining the strengths and limitations of preclinical model systems, including rodent models humanized mice, human induced pluripotent stem cells (iPSCs) 3D spheroids and brain organoids. This work emphasizes that research emanating from the varying preclinical experimental systems above should be leveraged and their complementary strengths integrated, coordinated, and considered collaboratively, to strengthen current knowledge, identify the remaining research gaps, and prioritize future research. We also emphasize the importance of rigorous, reproducible methodology and conservative interpretation of behavioral and functional outcomes. Discussion is presented on key translational bridges or connections that are urgently required to advance the field: bridging non-human model systems to humanized models, identifying and validating translational biomarkers, bridging in vitro and in vivo findings, and developing corroborative alternatives to animal models. It is our stance that integrating multiple complementary model systems, limiting erroneous behavioral inferences, relying on evolutionarily conserved circuits, and prioritizing robust and reproducible outcome measures will reduce failures in the translational pipeline and accelerate the development of meaningful therapies for individuals with NDDs.