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

Scientists studied brain tissue from people with autism and compared it to typical brains. They found that autistic brains don't prune (remove) excess brain connections as effectively during development, leading to too many local connections. They also found thinner protective coatings around nerve fibers, which may slow down brain communication. These differences in brain wiring might help explain some autism characteristics.

This postmortem electron microscopy study examined temporal lobe white matter development in 27 males with ASD compared to neurotypical controls (ages 2-44 years). Researchers analyzed axon density and myelin thickness in superior temporal and fusiform gyri regions. Key findings revealed that while neurotypical brains show typical age-related decreases in axon density (neural pruning) and increases in myelin thickness, ASD brains maintained higher densities of small axons in superior temporal regions and showed significantly thinner myelin sheaths on large axons across both regions. These differences suggest reduced neural pruning leading to local overconnectivity and impaired neurotransmission efficiency in ASD, potentially explaining connectivity differences observed in autism throughout development.

Findings suggest that connectivity differences in autism may stem from atypical white matter development involving reduced pruning and impaired myelination. This could inform understanding of why interventions targeting connectivity and communication may be beneficial early in development when neural plasticity is highest.

Small sample size of 27 individuals, male-only participants limiting generalizability to females with autism, postmortem tissue analysis cannot capture dynamic developmental processes, cross-sectional rather than longitudinal design, and methodology details not fully described in abstract.

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.