Abnormalities in neural connectivity and communication are evident in people with autism spectrum disorders (ASD). At 2 years of age, ASD white matter volume is approximately 10% larger and gray matter is 5% larger than in typically developing children. Structural and functional differences are most pronounced in "social brain" regions of the temporal lobe, including the superior temporal sulcus, fusiform gyrus, and amygdala. Although gray matter volume differences are often not detectable in adulthood, white matter abnormalities continue to be apparent throughout lifespan. In fact, over 40 diffusion tensor imaging studies (DTI) report prevalent white matter axonal abnormalities, and a recent study implicates specifically the mid-temporal portion of the inferior longitudinal fasciculus. However, the underlying cellular mechanisms that contribute to abnormalities in fiber tracts connecting temporal lobe regions remain largely unknown and unexplored. The goal of this research is to 1) investigate potential abnormalities in axonal ultrastructure that underlie aberrant temporal lobe white matter development in ASD brain tissue using electron microscopy (EM) and 2) correlate these findings with previously collected temporal lobe cellular and molecular data carried out on the same brains. A hypothesis has emerged suggesting that people with ASD have excess superficial/radiate white matter, which connects local brain regions, but a deficiency in deep, long distance axonal deep white matter. This theory can be tested by measuring myelinated axon thickness and density at certain distances from neuronal regions using EM. One recent frontal lobe EM study found a decrease in the number of long distance axons and an excessive number and higher density of short-range axons in white matter underlying anterior cingulate cortex. However, this phenomenon has yet to be explored in temporal lobe white matter regions. The goal of this study is to utilize EM to examine the axonal ultrastructure and neural connectivity underlying white matter abnormalities in temporal lobe, including the inferior longitudinal fasciculus, in the brains of people with ASD relative to typical development. We will use banked brain tissue sections previously prepared for studies of temporal lobe neuropathology. Our laboratory has developed a novel method to investigate axonal ultrastructure utilizing EM with fixed-frozen human brain tissue samples. Therefore, for the first time, we are able to explore the relationship of white matter abnormalities and cellular pathogenesis of ASD in adjacent histological sections within the same brain. This innovative study will allow us to create a comprehensive picture of ASD pathology in both neuronal (gray matter) and axonal (white matter) connectivity to elucidate the cellular basis for aberrant growth of the temporal lobe, identify neuropathological phenotypes in ASD, and guide development of targeted biological interventions.

Public Health Relevance

The goal of this research is to 1) investigate potential abnormalities in axonal ultrastructure that underlie aberrant temporal lobe white matter development and neural connectivity in ASD brain tissue using electron microscopy (EM) and 2) correlate these findings with previously collected temporal lobe cellular and molecular data carried out on the same brains. This study will create a comprehensive picture of ASD temporal lobe pathology and identify neuropathological phenotypes to guide development of treatment interventions.

Agency
National Institute of Health (NIH)
Type
Small Research Grants (R03)
Project #
1R03MH104735-01
Application #
8771308
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Gilotty, Lisa
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California Davis
Department
Psychiatry
Type
Schools of Medicine
DUNS #
City
Davis
State
CA
Country
United States
Zip Code
95618