Age-related differences in axon pruning and myelination may alter neural signaling in autism spectrum disorder

Neuronal connectivity is refined throughout development by the proliferation and pruning of axons in cerebral white matter, and progressive axon myelination that enables rapid communication across brain regions. Differences in connectivity have been observed in autism spectrum disorder (ASD), including changes in white matter volume and connectivity. In the prefrontal cortex, this includes imbalances between short- and long-ranging axons, consistent with a pattern of local hyperconnectivity, and long-range hypoconnectivity. Alterations in temporal lobe white matter development-critical for social behavior-may contribute to atypical neural connectivity.

We used electron microscopy to analyze 54 samples of temporal lobe white matter from 27 age-matched postmortem brains from males with ASD and neurotypical (NT) controls, ages 2-44 years. Defined regions of superficial (SWM) and deep (DWM) white matter were sampled from superior temporal (STG) and fusiform (FG) gyri. Axon density and myelin thickness were quantified, with axon size classified by inner diameter, to evaluate age-related differences between ASD and neurotypical brains.

In neurotypical control brains, total axon density significantly decreases with age in both STG and FG SWM. Although ASD cases show a similar trend, the density of small axons in STG is significantly higher than in controls. However, FG SWM in ASD shows no significant change in small-diameter axon density with age in this region. In neurotypical brains, myelin thickness of large-diameter axons increases significantly with age in STG and FG SWM. In contrast, large-diameter axons in ASD display significantly thinner myelin sheaths than controls across both STG and FG regions.

The temporal lobe exhibits atypical patterns of white matter development in ASD. In neurotypical individuals, decreased axon density in SWM with age reflects effective neural pruning and refinement of local and short-range connectivity. In contrast, individuals with ASD maintain a high density of small-diameter axons in STG SWM, suggesting reduced pruning that results in local overconnectivity. Moreover, myelin thickness in SWM does not increase with age in ASD, implying reduced efficacy of neurotransmission. These alterations in white matter ultrastructure may contribute to the atypical connectivity and neural communication observed in ASD across the lifespan.