Autism & the Brain: Subcortex Changes Take Center Stage

For decades, autism research has overwhelmingly focused on the cerebral cortex – the brain’s outer layer responsible for higher-level functions. Now, a pair of new preprints are challenging that long-held assumption, revealing significant dysregulation in deeper brain structures like the striatum and thalamus. This isn’t merely a shift in *where* we look, but a potential paradigm shift in *how* we understand and ultimately treat autism. The findings suggest that interventions targeting these subcortical regions could unlock new therapeutic avenues, moving beyond a sole focus on cortical plasticity.

The historical bias towards the cortex wasn’t accidental. Early gene-expression studies, limited by bulk-sequencing technology, often amplified signals from the expansive cortex, overshadowing more localized but potent activity in subcortical structures. As Tomasz Nowakowski of UCSF explains, there was an “inclination to stay away from brain-wide analyses” because researchers believed they already knew where to look. However, the advent of single-cell sequencing has changed the game. This technology allows for a far more granular analysis of gene expression, revealing that the strongest signals related to autism aren’t necessarily where researchers previously concentrated their efforts.

One study, led by Omer Bayraktar at the Wellcome Sanger Institute, used spatial transcriptomics to analyze gene expression in the prenatal human forebrain. The results were striking: 84 of 250 autism-linked genes showed strong expression in the thalamus, compared to just 10 in the rest of the cortex. The thalamus, a crucial relay station for sensory information, appears to be a key developmental hub for autism-related genetic activity. Simultaneously, Nowakowski’s team, studying mice with a 16p11.2 deletion (a common genetic alteration in autism), found dramatic changes in the striatum, specifically an increase in medium spiny neurons – cells also implicated in schizophrenia and other neuropsychiatric conditions. Further analysis of postmortem human brain tissue corroborated these findings, showing elevated levels of D1 dopamine receptor-expressing medium spiny neurons in autistic individuals.

This convergence of evidence is significant. It suggests that disruptions in striatal pathways, particularly those involving medium spiny neurons, may represent a common underlying mechanism across a range of neurodevelopmental and psychiatric disorders. Ricardo Dolmetsch of Stanford University notes this is “good news, in a way,” as it potentially links autism to better-understood conditions, opening doors for cross-disciplinary research and therapeutic strategies.

The Forward Look

The implications of these findings are far-reaching. The release of a complete atlas of the developing basal ganglia in mice, expected next year from the Allen Institute for Brain Science, will be a critical next step. This atlas will provide a detailed map of subcortical cell types and their development, allowing researchers to pinpoint the precise functions of different striatal cell populations and how they are disrupted in autism. However, the field must also address the potential for sex-specific differences, as preliminary research suggests that gene expression changes in medium spiny neurons may manifest differently in males and females.

Perhaps most importantly, these discoveries necessitate a re-evaluation of therapeutic approaches. Instead of solely focusing on cortical interventions, researchers should explore targeted therapies aimed at modulating thalamocortical and striatal circuits. Thomas Nickl-Jockschat of the University of Iowa argues against a “cluster-bombing” approach to neurotransmission, advocating for precision targeting of specific brain pathways. The next five years will likely see a surge in research focused on subcortical mechanisms in autism, potentially leading to the development of novel diagnostic tools and, ultimately, more effective treatments.