Deep Brain Structures Take Center Stage in new Autism Research
New research suggests that deep brain structures, particularly the striatum and thalamus, play a more notable role in autism than previously understood, potentially reshaping our approach to diagnosis and treatment. Two preprints released in November detail how these subcortical regions exhibit greater dysregulation in individuals with autism, challenging the long-held focus on the cerebral cortex.
For decades, the majority of gene-expression studies on autism have centered on the cerebral cortex. However, a growing body of evidence indicates that a more extensive understanding requires examining the entire brain.”There is more to autism than the cortex,” stated Omer Bayraktar, an investigator on one of the studies and cellular genetics group leader at the Wellcome Sanger Institute. “It’s time we pay strong attention to this.”
One study revealed that genes linked to profound autism are most active in the thalamus during mid-gestation. Gene expression in excitatory neurons was significantly altered, and genes linked to profound autism – were predominantly expressed in excitatory neurons.Gene expression in the germinal zones was largely confined to the medial ganglionic eminence, the birthplace of interneurons.
A parallel study, led by Tomasz Nowakowski of the University of California, San Francisco, investigated cell-type growth and gene-expression changes across five brain regions – the cortex, hippocampus, striatum, thalamus, and olfactory bulb – in mice lacking the chromosomal region 16p11.2. The striatum exhibited the most dramatic alterations in cellular composition, notably an increase in medium spiny neurons. These cells also displayed the most significant transcriptional changes.
While the role of medium spiny neurons in autism is still emerging, they have long been implicated in neuropsychiatric disorders. The research suggests that 16p deletions may disrupt striatal pathways also dysregulated in conditions like schizophrenia. Ricardo Dolmetsch, a professor of neurobiology at Stanford University, noted that this connection “is sort of good news, in a way. It points to other psychiatric diseases that we understand better.” Dolmetsch, who previously documented inflated populations of a subtype of medium spiny neurons in mice missing 16p11.2 in 2014, did not contribute to the new preprints.
Further analysis of postmortem striatal samples from 47 autistic individuals and 37 neurotypical controls revealed elevated numbers of medium spiny neurons expressing the D1 dopamine receptor in those with autism. The largest transcriptional changes were observed in a D1 subtype localized to the striosome, neurochemically distinct pockets within the striatum, with many of the dysregulated genes linked to autism or other neurodevelopmental conditions.
These findings align with another preprint reporting changes in medium spiny neurons in 16p11.2-deficient mice, which also highlighted sex-specific differences in gene expression and deficits in reward learning – a process dependent on corticostriatal circuits – in male mice but not females. While the new study did not detect similar sex differences,Ted Abel,chair of neuroscience and pharmacology at the university of Iowa,emphasized the need to consider a sex-specific perspective.
Ultimately, the evidence for subcortical involvement in autism is becoming increasingly compelling. Thomas Nickl-Jockschat, associate professor of psychiatry at the University of Iowa, argued that future therapeutic strategies should move away from broad neurotransmitter modulation and instead target specific circuits, including thalamocortical pathways.
However, significant questions remain regarding how changes in medium spiny neurons affect circuit function and whether different subtypes within the striosomes operate differently. Hongkui Zeng, director of the Allen Institute for Brain Science, is currently developing a complete atlas of the developing basal ganglia in mice, expected to be released next year, which could provide crucial insights into the functions of striatal cell types.
“I think this is going to be a major frontier for autism research,” Nowakowski concluded.
