Neuronal Profiles within the Subplate and Their Potential Contributions to Cortical Organization in Autism

Background:   As a neurodevelopmental disorder, autism spectrum disorders are associated with multiple cortical alterations.  Many of these alterations implicate neurodevelopmental events during the prenatal and perinatal periods, and these early changes have the potential to profoundly influence subsequent cortical activation and the establishment of cortical connectivity. One early and important cell population is found within the cortical subplate.  Neurons within the subplate play a role in neuronal patterning within the cortex, and are responsible for guiding thalamo-cortical and cortico-thalamic connections.  In addition, they provide early coordinated activation of the overlying cortical layers and, in the adult, may serve an additional role as modulators of cortical afferents.  Although many subplate neurons undergo apoptosis during development, in primates a substantial proportion of these cells are retained into adulthood.  Adults with autism show a diffuse organization within the subplate region and excess neuronal profiles.  These excess profiles could be neurons that did not migrate into the overlying cortex or they could be vestiges of the subplate population that have not undergone apoptosis.

Objectives:   The goal of the present study was to quantitatively assess the density of neurons in the cortical subplate of individuals with autism relative to their neurotypical counterparts.

Methods:   Postmortem tissue samples from the superior parietal lobe (BA 7) were acquired from twelve subjects (6 autistic, 6 neurotypical; age-matched). Cryostat sections were processed for neuronal nuclei (NeuN) immunohistochemistry and were subsequently digitized and subjected to an automated identification procedure of the cortical layer VI-white matter boundary to ensure reliable definition of the superficial white matter and placement of the sampling boxes.  In addition, Golgi-staining was utilized to provide a morphological evaluation of this cell population in ASD subjects. 

Results:   Our results show a large systematic increase in the density of NeuN+ cells in the cortical subplate in autism relative to age-matched neurotypicals (F(1,119.42) = 93.1, p < .001; Cohen’s d = 1.56). Furthermore, four of the six autistic subjects showed an average subplate neuron density >1.5 standard deviations from the mean of the neurotypical subjects.  Golgi staining demonstrates the presence of both multipolar and fusiform cell types that are morphologically similar to subplate neurons.

Conclusions:  

Neurons of the subplate play a critical role during development in guiding afferent and efferent connectivity to the cerebral cortex.  Although many of these cells are lost during development they continue to play a critical role in gating cortical activity in the adult.  Like ASD, the presence of excessive neurons subjacent to the cerebral cortex has been shown in other neurological disorders such as schizophrenia (Eastwood & Harrison, 2003) and epilepsy (Emery et al., 1997).  In these conditions it has been hypothesized that these neurons contribute to disconnectivity in the mature brain (Kostovic et al., 2011).  As such, excessive neuronal profiles in the subplate may be a contributor to both abnormal cortical development and disconnectivity in the ASD brain, and could potentially play a future role in prenatal diagnosis through imaging methods.