Evidence for dysregulation of axonal growth and guidance in the etiology of ASD

Abstract

Current theories concerning the cause of autism spectrum disorders (ASDs) have converged on the concept of abnormal development of brain connectivity. This concept is supported by accumulating evidence from functional imaging, diffusion tensor imaging, and high definition fiber tracking studies which suggest altered microstructure in the axonal tracts connecting cortical areas may underly many of the cognitive manifestations of ASD. Additionally, large-scale genomic studies implicate numerous gene candidates known or suspected to mediate neuritic outgrowth and axonal guidance in fetal and perinatal life. Neuropathological observations in postmortem ASD brain samples further support this model and include subtle disturbances of cortical lamination and subcortical axonal morphology. Of note is the relatively common finding of poor differentiation of the gray–white junction associated with an excess superficial white matter or “interstitial” neurons (INs). INs are thought to be remnants of the fetal subplate, a transient structure which plays a key role in the guidance and morphogenesis of thalamocortical and cortico-cortical connections and the organization of cortical columnar architecture. While not discounting the importance of synaptic dysfunction in the etiology of ASD, this paper will briefly review the cortical abnormalities and genetic evidence supporting a model of dysregulated axonal growth and guidance as key developmental processes underlying the clinical manifestations of ASD.

Reduced cortical thickness and its association with social reactivity in children with autism spectrum disorder

“…If the consistently reported early cortical overgrowth in ASD consequently reflects deficits in synaptogenesis with earlier, too strong or otherwise disturbed synaptic pruning processes, this will lead to accelerated cortical thinning at later ages and further illustrates the disruption of normal developmental trajectories in ASD. However, not only synaptogenesis, but also axonal growth (Gilman et al, 2011;McFadden and Minshew, 2013) and axon pathfinding (Sbacchi et al, 2010), may be different, potentially leading to alterations in cortical development. Table 3 Means and standard deviations of average cortical thickness as well as F-and significant p-values of frontal, temporal and parietal structures (in mm) of the left (L) and right (R) hemisphere in subjects with autism spectrum disorder (ASD) and healthy controls (HC), ASD oHC.…”

Development, evolution and pathology of neocortical subplate neurons

“…Heterotopias, including some in the white matter, were found in child and adult cases 137 . MRI of brains of patients with autism spectrum disorders revealed an indistinct boundary between grey and white matter, possibly also indicating supernumerary subplate neurons 136,138,139 . However, it should be noted that epilepsy is a common co-morbidity of autism, and some overlap between the underlying brain malformations may be expected.…”

Joint Attention Impairment in Autism: Clinical Picture, Rationale and Functional MRI Findings

“…This disrupted connective circuitry in the brain was proposed by Just et al [51] in the cortical underconnectivity theory, describing a lower communication bandwidth between frontal and posterior temporal areas in autistic compared to control participants. On the other hand, McFadden and Minshew [52] pointed to local overconnectivity in the form of consistent finding of excess interstitial neurons that reflects failure of appropriate developmental apoptosis and leads to improper brain connective function.…”