Nature: The most comprehensive molecular study of the autistic brain

Guide:

Autism is a type of autistic spectrum disorder (ASD), which is a representative disease of pervasive developmental disorder, which seriously affects patients' social, behavioral and verbal skills
.
According to statistics, there are currently more than 10 million autistic people in China (about 1 in every 68 children).

In recent years, with the deepening of research on autism, people have gradually realized that autism is a diffuse central nervous system developmental disorder, which is affected
by certain genetic factors and a variety of environmental factors.
Although there have been many studies on the causes of autism from different perspectives such as molecular genetics, neuroimmunity, functional imaging, neurochemistry, and neuroanatomy, there is still no hypothesis that can fundamentally explain the cause
of autism.

Neuropsychiatric disorders often lack a well-defined brain pathology; This is especially true for autism – compared to neurological disorders such as Alzheimer's disease and Parkinson's disease, autism has always lacked a clear pathological explanation, which makes it more difficult
to develop effective treatments.
Recent studies have shown that neuropsychiatric disorders involve regulatory disorders at the molecular level, manifested by transcriptomic and epigenetic alterations; For autism spectrum disorder (ASD), this molecular pathology involves upregulation of microglia, astrocytes, and neuroimmunity-related genes, downregulation of synaptic genes, and attenuation
of gene expression gradients in the cortex.
However, do these changes occur only in cortical associated areas, or in a wider area? It is still unknown
.

On November 2, the UCLA research team published a research paper in the journal Nature entitled "Broad transcriptomic dysregulation occurs across the cerebral cortex in ASD"; The study comprehensively characterizes autism spectrum disorder (ASD) at the molecular level, demonstrating the most comprehensive understanding
to date of how autism affects the brain at the molecular level.

The landmark result of more than a decade of work

Dr.
Daniel Geschwind, professor of human genetics, neurology and psychiatry at UCLA, led the study
.
"This work represents a signature result of
more than a decade of work by many of our lab members.
Such a comprehensive analysis of the autistic brain is necessary
.
Now, we can finally gradually begin to understand the state of the autistic brain at the molecular level – similar to Parkinson's, Alzheimer's and other brain diseases such as stroke – which provides us with a molecular pathway to understand autism and will accelerate the development of
related treatments.
”

Previous research has shown that at the molecular level, different brain regions in autistic people tend to be more uniform
than in non-autistic people.
In other words, in non-autistic people, the difference in gene expression between the posterior and anterior regions is more pronounced; The differences for autistic people are relatively modest
.
Other studies have found another "molecular feature" unique to autism – reduced expression of genes associated with neurons and synapses; Increased
expression of genes associated with astrocytes, microglia, and immune processes.
But these features are based on small samples limited to the associated regions of the temporal and frontal lobes, which control higher-order functions such as cognition, language, and social behavior.

The new study confirms and extends these previous results
.
Its analysis of 11 different cortical regions in all four lobes (frontal, parietal, temporal and occipital) showed that differences in gene expression for autism were most pronounced in two sensory regions located at the back of the brain: the Brodmann region 17 (BA17), which processes visual information, and the Brodmann region7, which integrates visual and motor information7
.

Differences in gene expression in autism are most pronounced in Brodmann regions 17 and 7 at the back of the brain

"Surprisingly, these autism-associated genes are expressed across the cortical surface, particularly in the primary visual cortex and major sensory regions, rather than the associated regions," said Arnold Kriegstein, a professor of neurology at the University of California, San Francisco.

The study analyzed 725 postmortem brain samples
from 49 autistic people and 54 non-autistic controls.
They found that the brains of autistic people showed dysregulation in 4,223 genes and 9,474 genotypes — mRNAs from the same part of the genome, often with different protein-coding sequences
.

Dysregulated genes are also not randomly distributed in different cellular processes
.
Dr.
Geschwind said: "They belong to very specific cell types (especially neurons, oligodendrocytes and microglia); Influence very specific biological processes, so they represent coordinated procedures
.

Across the cortex, 13 gene modules (genomes exhibiting similar expression patterns) have regional differences; All of these modules follow a front-to-back gradient, meaning they are most dysfunctional
at the back of the brain.
In BA17, dysregulated genes include SOX4 and SOX11, two transcription factors that promote neuronal differentiation, and SCN9A, which encodes a sodium channel
important for cell signaling.

In this region alone, there are more than 3,200 genes differentially expressed
compared to non-autistic brain tissue.
A gene called ETV4 encodes a transcription factor that helps dendrites develop and connect
with neurons.
In autistic brain samples, genes regulated by ETV4 were also reduced
in the BA17 region.

The gist of RNA sequencing is simple: extract RNA from brain tissue sections, convert them into DNA, and then sequence
it.
But it has a big caveat: Researchers can't always be sure that "dysregulated genes" are caused by actual molecular changes within cells, rather than reflecting differences
in the number of cell types.

When Geschwind presented the paper, one of the reviewers said the work was unremarkable because the differences in gene expression were "clearly all due to cellular makeup.
"

To debunk this idea, Geschwind's team sequenced
RNA from more than 250,000 individual cells from six autistic and six non-autistic people.
The analysis showed that autistic patients had slightly more astrocytes and excitatory neurons, but the difference in the number of cell types was insufficient to explain these findings
.

"The question that this study raises at the single-cell level is whether the changes we see are simply due to changes in cellular composition, or whether the molecular pathways and signaling that occur within the cell actually change," Geschwind said.

”

Future exploration directions

Dr.
Geschwind's team is now testing various hypotheses to explain their results
.
Because dysregulated genes appear primarily in brain regions that receive instructions from the thalamus, the thalamus transmits sensory information from the periphery, "some of which may underlie
the sensory hypersensitivity responses that people see in autism.
" ”

They are expanding their analysis to include the thalamus
.
"If our hypothesis is correct—which reflects sensory input to the cortex—then we expect the thalamus, which is the main relay of sensory information in the brain, to show a similar pattern
.
"

Dr.
Geschwind says one of the next steps is to determine whether researchers can use computational methods to develop therapies based on reversing gene expression changes the researchers found in ASD, which in turn can be modeled using organoids to better understand their mechanisms
.