THE ASD LIVING BIOLOGY: FROM CELL PROLIFERATION TO CLINICAL PHENOTYPE

Abstract

Autism spectrum disorder (ASD) has captured the attention of scientists, clinicians and the lay public because of its uncertain origins and striking clinical symptoms. A spectrum of candidate etiologies including evidence of genetic variants, present a perplexing picture of ASD origins. Furthermore, reliance on postmortem and other neurobiological evidence from older ASD cases limits understanding of its origins and early developmental processes. Arguably the least studied and understood period in ASD is prenatal and early postnatal, when ASD biology begins in a child. Missing, therefore, is what we call the ASD Living Biology. This is a conceptual and paradigm shift towards a focus on the abnormal prenatal processes underlying ASD within each individual. The concept emphasizes the specific need for foundational knowledge of a child’s development from abnormal prenatal beginnings to early clinical stages; and the ASD Living Biology paradigm seeks this knowledge by linking genetic and in vitro prenatal molecular, cellular and neural measurements with early in vivo postnatal molecular, neural and clinical presentation and progression in each ASD child. Within-child ASD Living Biology is a research concept we coin here that advocates the integration of that prenatal and postnatal information to generate individualized and group-level explanations, clinically useful prognoses, and effective treatments for ASD. Towards this effort, we review recent studies through the lens of ASD Living Biology. This view supports the theory of ASD as a progressive prenatal dysregulation of brain growth, spanning nearly all of prenatal life. ASD begins as early as the 1 ^st and 2 ^nd trimester with disruption of cell proliferation and differentiation in the brain. It continues with disruption of migration, laminar organization, cell growth, neurite outgrowth, synaptogenesis, receptor and neurotransmitter development, and assembly of functional neural networks. Among the most commonly reported high confidence ASD genes, 94% express during prenatal life and affect these developmental processes, with a majority affecting proliferation/differentiation and synapse development, potentially influenced by disrupted PI3K-AKT/RAS-ERK signaling. ASD toddler-derived cellular experiments show dysregulation of cell cycle, excess cell proliferation, reduced neuronal and synaptic maturation, and a 6-fold decrease in synchronized neural network activity. Such defects underlie atypical experience-dependent development of large-scale social and communication networks. Furthermore, variation in dysregulation of cell proliferation correlates with variation in a child’s brain growth, due to either ASD brain undergrowth with fewer and more functionally impaired neurons, or overgrowth with an excess of poorly synchronized neurons. It remains unclear how genetic factors cause these changes in ASD. Maternal immune activation (MIA) offers one possible non-genetic etiology, exhibiting a similar progression with increased proliferation and ASD-like neurodevelopmental defects and behavioral deficits. To address the prenatal and early postnatal molecular, cellular and anatomical changes in ASD, entirely new treatment concepts are needed. This also requires coordinated in vivo and in vitro ASD living biology research to unravel the heterogeneity in etiology, severity, developmental timing, and neural system distribution of disrupted development. We advocate that through an ASD living biology approach, relationships between prenatal stages, early-age postnatal brain growth and function, clinical presentation and progression, and treatment outcome may be defined at the individual level, thus enabling the development of precision medicine approaches with truly beneficial interventions.