Fig. 8
From: The ASD Living Biology: from cell proliferation to clinical phenotype
ASD is a multistage, progressive disorder of prenatal brain development. ASD children show a continuum of disorder severity because a wide range of heterogeneous insults can affect brain development in a not fully deterministic way. We propose the general theory that ASD arises from disruption of gene regulatory circuits with multiscale, hierarchical consequences on brain development starting from very early fetal stages. One possible prenatal trajectory of ASD is illustrated here. As compared with four fetal stages illustrated in typical development (lower panel; increasing fetal age from left to right), this ASD trajectory begins in the 1st and 2nd trimesters with abnormally high rates of proliferation; this results in excess neural precursor cells (ASD first panel). Disorder continues with disruption of migration, laminar disorganization, reduced cell growth, and reduced neurite outgrowth, resulting in neurons with a 10-fold decrease in spontaneous neural activity (ASD second panel). At still later stages, ASD neurons show defects in synaptogenesis, receptor and neurotransmitter development (ASD third panel). This deviant development of neurons leads to abnormal neural circuitry with a 6-fold decrease in synchronized bursts of neural network activity (ASD fourth panel). This also illustrates that ASD pathogenesis is not set at one point in time and does not reside in one process, but rather is a cascade of pathogenic processes. Different causes and prenatal times of insult combined with individual-dependent background genetics may alter details of developmental trajectories, resulting in differences in number, size and type of neurons in different cortical layers as well as number and functionality of synapses. This fetal heterogeneity leads to post-natal heterogeneity in neural circuits, behavior and clinical outcomes. Discovery of prenatal causes, processes and trajectories as they occur in children with ASD requires a paradigm shift: the ASD Living Biology approach. Courtesy of Eric Courchesne and Vahid H. Gazestani
