Beyond categorical boundaries: Common molecular and cellular pathways in autism spectrum disorder and schizophrenia

Historically, ASD and schizophrenia have been classified as two distinct disorders, one being a neurodevelopmental disorder and the other a psychotic disorder. Recent studies, however, suggest that there may be substantial overlap between these disorders. Here, we will discuss some of the biological mechanisms involved in the development of these diseases that show similarities. These include dysregulation of the dopaminergic, serotonergic, glutamatergic, GABAergic, and acetylcholinergic systems; changes in BDNF signaling; histamine dysregulation; microglial activation; neuroinflammation; complement-mediated synapse elimination; gut-brain axis signaling; and endocannabinoid system dysfunction. It is important to note that the aforementioned biological mechanisms are present in several CNS disorders, such as major depressive disorder, Alzheimer's disease, and multiple sclerosis. While it is true that other CNS disorders share the same biological mechanisms as ASD and schizophrenia, the similarity between these disorders stands out for a particular reason. First, the biological mechanisms present in ASD and schizophrenia are significantly similar; second, their heritability is highly consistent; third, they have similar developmental trajectories; fourth, they exhibit similar circuit-level pathology; fifth, they share bidirectional epidemiological risks; and sixth, they follow a neurodevelopmental continuum. Recognizing this overlap has potential implications for early detection, biomarker development, and transdiagnostic treatment strategies, including repurposing medications such as memantine, α7-nicotinic agonists, and anti-inflammatory agents. However, longitudinal studies are needed to determine whether early targeting of shared pathways modifies long-term psychosis risk in ASD.