Autism as a sequence: From heterochronic germinal cell divisions to abnormalities of cell migration and cortical dysplasias

Abstract

The considerable heterogeneity in the number and severity of symptoms observed in autism spectrum disorders (ASD) has been regarded as an obstacle to any future research. Some authors believe that clinical heterogeneity results from the complex interplay of the many genetic and environmental factors that themselves define a condition as multifactorial. However, it is important to note that neuropathological findings in both idiopathic and syndromic autism suggests a single pathophysiological mechanism acting during brain development: the heterochronic division of germinal cells and subsequent migrational abnormalities of daughter cells to their target fields. Multiple exogenous (e.g., viruses, drugs) and endogenous (e.g., genetic mutations) factors are known to disrupt the division of germinal cells and provide for an autism phenotype. The variety of endogenous and exogenous factors, their timing of action during brain development, and the genetic susceptibility of affected individuals (a Triple Hit hypothesis) may all account for the clinical heterogeneity of ASD.

Merging Data from Genetic and Epigenetic Approaches to Better Understand Autistic Spectrum Disorder

“…Because of the genetic and symptomatic heterogeneity, ASD is also thought to be etiologically heterogeneous. However, as recently argued [ 19 ], neuropathological findings in both idiopathic and syndromic ASD support instead a common pathophysiological mechanism. The author of this study argues that multiple exogenous and endogenous factors disrupt cell division in the brain which leads to the pathological changes observed in ASD.…”

Perturbed Wnt signaling leads to neuronal migration delay, altered interhemispheric connections and impaired social behavior

“…Here we demonstrate that a transient decrease of canonical Wnt signaling during glia-guided locomotion delays but does not permanently arrest migration of CPNs, and these neurons with Wnt LOF eventually reach their final destination in layer 2/3. It has been proposed that abnormal neuronal migration contributes to the pathogenesis of neurodevelopmental disorders such as ASD, which is characterized by poor social interactions, repetitive behavior and altered communication 8 , 11 , 12 , 45 . In support of this hypothesis, we show that delayed migration of a subset of CPNs is associated with long-term behavioral abnormalities ranging from sensory dysfunction to ASD-like social deficits and compulsive behavior.…”

The modular organization of the cerebral cortex: Evolutionary significance and possible links to neurodevelopmental conditions

“…These disorders, or minicolumnopathies, are characterized by shared clinical features (Table 1) The presence of minicolumnar abnormalities in autism is suggestive of a neuronal migration disorder. The findings have proven to be of significance for their explanatory and predictive powers (e.g., changes in the gray-white matter ratio, gamma frequencies, and excitatory/inhibitory bias) as well as having given rise to a potential therapy aimed at core pathological features of the condition (i.e., transcranial magnetic stimulation) (Casanova, 2014a(Casanova, , 2014bCasanova, Sokhadze, Opris, Wang, & Lo, 2015;Sokhadze et al, 2009).…”