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. 2014 Jul;83(1):32-8.
doi: 10.1016/j.mehy.2014.04.014. Epub 2014 Apr 13.

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

Manuel F Casanova  1
Affiliations

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

Manuel F Casanova. Med Hypotheses. 2014 Jul.

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.

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Conflict of interest statement

CONFLICT OF INTEREST STATEMENT

The author has no conflicts of interest to disclose.

Figures

Figure 1
Figure 1
A schematic of the concatenated pathology proposed for autism spectrum disorders. Idiopathic cases exhibit abnormalities of germinal cell divisions, migration and cortical dysplasias. Syndromic cases exhibit a known cause and additional manifestations. In the absence of a known cause (symbolized by an X on the figure) we tend to speak of cases as syndromes rather than sequences.
Figure 2
Figure 2
Coronal section of the human brain during embryonic development. The clear arrowheads illustrate the tangential migratory pathway of cells (future interneurons) from the lateral and medial ganglionic eminences (LGE, MGE) to the cortical plate. Interneurons may also originate from the retrobulbar neuroepithelium of the lateral ventricle and from the cortex itself. Those interneurons fated for the cortex acquire a superficial and deeper pathway in order to avoid the embryonic striatum. A set of dark arrowheads illustrate how neuroblasts migrate out of the ventricular zone and into the cortical plate (future pyramidal cells) following a radial pathway. An excitatory/inhibitory imbalance may result from desynchronization of cells as they undertake their radial and tangential migrations. Because interneurons are generated at such distant sites their migration may be susceptible to disruption from a large variety of sources.
Figure 3
Figure 3
Manifestations of syndromic autism spectrum disorders exhibit a common neuropathology. Abnormalities in germinal cell divisions may lead to changes in corticocortical connectivity, seizures and sensory/motor abnormalities (28).
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