https://orcid.org/0000-0002-1496-9889
Abstract
Researchers are increasingly investigating the developmental origins of white matter alterations in autism spectrum disorder (ASD). A recent review by Canada, Evans, and Pelphrey highlights the roles of oligodendrocytes and microglia in ASD-related white matter abnormalities. Evidence suggests that ASD risk genes impact oligodendrocyte development and myelination, while microglia dysfunction due to immune challenges may further disrupt white matter formation. Emerging studies link neuroinflammation to altered white matter trajectories, supporting early intervention strategies. Future research integrating neuroimaging, genetics, and immune profiling may enhance our understanding and facilitate the development of targeted neuroimmune therapies for ASD.
Which are the developmental causes of white matter alterations occurring in the brain of people with autism spectrum disorder (ASD)? This is the question that Canada, Evans, and Pelphrey address in their review in the current issue of Cerebral Cortex.
A large number of genes are associated to ASD (https://gene.sfari.org/); most of these genes code for proteins involved in synaptic signaling, transcriptional/post-transcriptional mechanisms, and cell adhesion, and control the birth and differentiation of neuronal and glial cells, neuronal migration, as well as formation and maintenance of neuronal connections during neurodevelopment (De La Torre-Ubieta et al. 2016). Evidence collected in the last 20 years clearly indicates that white matter development is profoundly altered in ASD brains. Magnetic resonance imaging studies revealed an altered structure of white matter tracts in multiple brain regions of ASD subjects. Even more interestingly, a typical trajectory of white matter development is observed in ASD as compared to age-matched, neurotypical peers: an initial hypermyelination at early postnatal ages is followed by marked hypomyelination, which generally lasts throughout lifespan (Canada et al. 2025, this issue, and references therein). Cellular mechanisms underlying these anatomical alterations begin to be understood.
In their review, Canada and coworkers focus on the role of oligodendrocytes and microglia in abnormal white matter formation in ASD pathogenesis. Several ASD risk genes are expressed in oligodendrocytes, and control different steps of oligodendrocyte development involved in white matter formation (Alonso-Gonzalez et al. 2019). It is therefore not surprising that the expression of oligondendrocyte-specific genes (including those previously associated to ASD) is altered in the brain of idiopathic mouse models of ASD (Dalton et al. 2024). In addition, microglia-specific genes have been associated with ASD (Ishizuka et al. 2017) and their mutation results in ASD-like phenotypes in mice (Zhan et al. 2014; Filipello et al. 2018). Microglia, the brain-resident immune cells, are known to release growth factors that control oligodendrocyte differentiation and myelin gene expression. However, genetic ablation of microglia in mice does not impair myelination and white matter formation during development, but results in hypermyelination, suggesting a role for microglia in preventing the excessive formation of white matter (McNamara et al. 2023). Last, but not least, immune system challenges during development alter the production of cytokines by microglia cells, potentially impacting on the proper development of white matter.
On the basis of such evidence, Canada and coworkers propose a model to explain the complex interrelation between neuroinflammation, white matter development, and ASD pathogenesis. According to this model, challenges to the immune system occurring during neurodevelopment may result in microglia dysfunction and subsequent impairment of oligodendrogenesis and myelination, leading to aberrant control of social and sensorimotor behaviors as observed in ASD. This is an intriguing hypothesis, which definitely deserves further investigation. As proposed by Canada and coworkers, several avenues might be explored to better understand the tight link between neuroinflammation, white matter, and ASD.
1) Immune system challenges during neurodevelopment impact synaptic function and myelination. A substantial body of evidence supporting this notion comes from results obtained in animal models of maternal immune activation. While the appropriateness of these models is unquestionable, other experimental approaches might contribute to understand the time-course and impact of neuroinflammation in ASD. For example, mutations in syndromic ASD genes result in chronic inflammation in mice (Pangrazzi et al. 2024, 2025). However, little is known about the time of appearance of neuroinflammation in these and other ASD models, an aspect that should be thoroughly investigated in future studies in order to identify early windows of intervention.
2) Increased levels of proinflammatory cytokines have been detected in the peripheral blood of ASD subjects (reviewed in Estes and McAllister 2016; Pangrazzi et al. 2020). In the near future, longitudinal studies combining neuroimaging, genetic, and immune profiling might contribute to elucidate the causal relationship between immune dysfunction and altered trajectories of white matter development in ASD. In this respect, a recent (still undergoing peer-review) study using neuroimaging and transcriptomic datasets from large cohorts of ASD mouse models and human ASD subjects revealed a tight correlation between functional hyperconnectivity and immune dysfunction in ASD (Pagani et al. 2025). Thus, early detection of functional hyperconnectivity might be predictive of chronic neuroinflammation (and vice versa) in ASD subjects, strengthening the rationale for early pharmacological intervention.
3) Indeed, neuroimmune-targeted interventions could open new avenues for early treatment of ASD and related neurodevelopmental disorders. Recent findings showed that chronic inflammation can be rescued by systemic treatment with the anti-oxidant/anti-inflammatory drug N-acetylcysteine (NAC) treatment in adult mice lacking ASD-risk genes (Pangrazzi et al. 2024, 2025). On the other hand, contrasting evidence supports the efficacy of NAC against ASD symptoms in humans (see references in Pangrazzi et al. 2025). It is essential to recognize that ASD varies widely among individuals, so not everyone with ASD may experience increased oxidative stress and inflammation. Thus, a careful stratification of ASD subjects based on quantifiable parameters (e.g., blood levels of inflammation markers) should be available prior to investigating the efficacy of neuroimmune-targeted treatments.
4) Finally, the identification of specific cell populations involved in white matter malformations (such as the above-mentioned oligodendrocytes and microglia) might guide future large-scale drug screenings to identify more effective therapies for ASD.
As schematized in Fig. 1, the available evidence supports the idea that investigating the developmental causes of white matter alterations will offer new opportunities for therapeutic approaches against ASD and other neurodevelopmental disorders.
Neuroimmune contributions to white matter alterations in ASD.
Author contribution
Yuri Bozzi (Conceptualization, Funding acquisition, Writing—original draft, Writing—review & editing).
Funding
This work was funded by the Autism Research Institute (ARI 2023 award to Y.B.).
Conflict of interest statement: The author declares no conflict of interest.
