The neuropathology of autism: defects of neurogenesis and neuronal migration, and dysplastic changes

TLDR

Autism presents with social, communicative, and repetitive behavior deficits, and early brain overgrowth, neuronal growth delays, and minicolumn abnormalities suggest widespread regional changes. The study aimed to map focal developmental defects and pinpoint brain regions most susceptible to abnormalities in autism. Researchers examined formalin‑fixed hemispheres from 13 autistic and 14 control brains, sectioned at 200 µm, stained with cresyl violet, and performed neuropathological assessment. Nearly all autistic brains (92%) exhibited focal dysplastic changes—including subependymal thickening, heterotopias, multifocal cortical and cerebellar dysplasia—demonstrating multiregional dysregulation of neurogenesis, migration, and maturation.

Abstract

Autism is characterized by a broad spectrum of clinical manifestations including qualitative impairments in social interactions and communication, and repetitive and stereotyped patterns of behavior. Abnormal acceleration of brain growth in early childhood, signs of slower growth of neurons, and minicolumn developmental abnormalities suggest multiregional alterations. The aim of this study was to detect the patterns of focal qualitative developmental defects and to identify brain regions that are prone to developmental alterations in autism. Formalin-fixed brain hemispheres of 13 autistic (4–60 years of age) and 14 age-matched control subjects were embedded in celloidin and cut into 200-μm-thick coronal sections, which were stained with cresyl violet and used for neuropathological evaluation. Thickening of the subependymal cell layer in two brains and subependymal nodular dysplasia in one brain is indicative of active neurogenesis in two autistic children. Subcortical, periventricular, hippocampal and cerebellar heterotopias detected in the brains of four autistic subjects (31%) reflect abnormal neuronal migration. Multifocal cerebral dysplasia resulted in local distortion of the cytoarchitecture of the neocortex in four brains (31%), of the entorhinal cortex in two brains (15%), of the cornu Ammonis in four brains and of the dentate gyrus in two brains. Cerebellar flocculonodular dysplasia detected in six subjects (46%), focal dysplasia in the vermis in one case, and hypoplasia in one subject indicate local failure of cerebellar development in 62% of autistic subjects. Detection of flocculonodular dysplasia in only one control subject and of a broad spectrum of focal qualitative neuropathological developmental changes in 12 of 13 examined brains of autistic subjects (92%) reflects multiregional dysregulation of neurogenesis, neuronal migration and maturation in autism, which may contribute to the heterogeneity of the clinical phenotype.