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.

Keywords: autism spectrum disorders; axonal guidance; connectivity; neuritic outgrowth; subplate.

FIGURE 1

Sources of evidence for a model of dysregulated axonal development in ASD. A broad gap exists between the clinical manifestations of ASD and growing list of genetic candidates; a gap only incompletely bridged by a general model of altered connectivity. A significant component of dysregulated axonal development (polarity, outgrowth, and guidance/targeting should be considered in constructing a model of ASD etiology that encompasses all of the clinical, functional, structural, and genetic observations.

FIGURE 2

Key molecular pathways of axonal development implicated by genetic studies. Genome-wide association and CNV studies have implicated numerous molecules and molecular pathways involved in neuritic outgrowth, neuronal polarity, axonal-dendritic targeting, and synaptogenesis. Many of these are common to multiple related developmental processes as they serve the more general functions of providing positional information. This recycling phenomenon may explain the link between arealization/proliferation abnormalities, axonal and dendritic abnormalities, and synaptic dysfunction in ASD.