From molecules to behavior: An integrative theory of autism spectrum disorder

Abstract

Autism spectrum disorder (ASD) comprises a group of neurodevelopmental disorders for which various theories have been proposed. Each theory brings valuable insights and has experimental evidence backing it, yet none provides an overarching explanation for each of the pathological aspects involved in ASD. Here we present an integrative theory of ASD, centered on a sequence of events spanning from the molecular to the behavioral level. We propose that an abnormality in the interplay between retinoic acid and sex hormones predisposes an individual to specific molecular malfunctions. In turn, this molecular syndrome generates an altered brain connectivity between the cerebellum, the midbrain dopaminergic areas, and the prefrontal cortex. Lastly, this disconnection would generate specific behavioral traits traditionally involved in ASD. Therefore, this paper represents a step forward in unifying different levels of pathological features into novel integrated testable hypotheses.

Keywords: Cerebellum; Prefrontal cortex; RORA; Retinoic acid; Testosterone; Ventral tegmental area.