Detection of leading developmental defects in brains of autistic subjects

Background: In autism, a plethora of genetic and non-genetic factors can result in different patterns of neuropathological structural equivalents. A majority of these structural modifications are detectable only with stereological methods. We hypothesized that reduced volumes of the neuronal body and nucleus are the most consistent markers of developmental pathology detectable in autism.

Objectives: This project focuses on establishing protocols for detection of markers of developmental abnormalities of the neuron, neuronal networks within brain structures, and neuronal circuits integrating brain structures in morpho-functional units.

Methods: We examined brains of 14 subjects with autism and 14 controls by using routine neuropathological methods, electron microscopy, and morphometry.

Results: We observed a broad spectrum of neuropathological changes. However, the most consistent was reduced size of neurons. In 4-7 year old autistic children, Purkinje cells were smaller by 38%. Neurons in the dentate nucleus were reduced by 26%; in amygdala by 24%; in nucleus accumbens by 41%; in caudate by 20%; and in putamen by 27%. Neurons in the nucleus of the facial nerve and nucleus olivaris did not show a significant difference from controls. In many brain subdivisions, a partial or complete correction of the size of neurons was observed in late childhood or adulthood.

Conclusions: We found evidence of disproportional development of the cell nucleus and cell body, and dramatic delay of growth of both neurons and neuronal networks. The increase of neuronal volume observed in late childhood may contribute to behavioral improvement in some patients. This study will help to identify the potential target of treatment for developmental deficits in autism.

The Harvard Brain Tissue Resource Center (R24-MH 068855), and Brain and Tissue Bank at the University of Maryland, Baltimore provided tissue. Autism Tissue Program coordinated tissue acquisition.