Look for the disrupted brain signals behind autism

Understanding the underlying causes of autism spectrum disorder depends in part on figuring out which cells in the brain have disrupted signaling patterns and when this disruption
occurs during nervous system development.

New findings on the genetic risk of autism, found in a mouse model, support the idea that losing a specific gene interferes with cells
in the brain that inhibit signaling.
Although these cells are fewer in number than other neurons, and their signals don't travel far, they have a huge impact
on information transmission patterns inside the brain and in other parts of the body.

Researchers at The Ohio State University found that deleting copies of the autism risk gene Arid1b from specific brain cells reduced the number of suppressor cells and reduced signaling
between suppressor cells and the excitatory cells they helped control.
Previous studies have shown that in mouse models with autism, a reduction in inhibitory signals leads to a range of autism-related behaviors
.

In different experiments, the scientists found that the signal changes associated with suppressor cells, seen shortly after birth in mouse models of the same autism spectrum disorder (ASD) gene, may not be enough to interfere with normal brain development
driven by other genes.

Studying the effects of disease risk genes on brain circuits is meant to pave the way for possible treatments, but the study also provides insight into how normal circuits work, because "in many cases, this remains a mystery," said senior author Jason West, assistant professor of neuroscience at The Ohio State University School of Medicine and senior author
.

"These circuits are a critical level of analysis for understanding brain function — not only to understanding why things go wrong in neurodevelopmental disorders, but also to understanding how normal circuits work
," West said.
"We wanted to know what neurodevelopmental disorders can tell us about how normal circuits work, and how this can tell us how to repair broken circuits
.
" The research poster was presented
today (Monday, November 14, 2022) at the Neuroscience 2022 Conference.

There are many genes associated with the risk of autism spectrum disorder, which is one of
the reasons autism is so difficult to study and treat.
In fact, in a recent data-mining RNA sequencing study, West's lab created the first list of
genetic tissues associated with synapses, vectors for cell-to-cell circuit transmission.

"We want to provide clues to see if we can consider treatments for autism that can be repaired
throughout the brain if we tweak a single gene," he said.
Unfortunately, we found this unlikely
.
Autism risk genes are not concentrated in
one specific group.
But we did find many in suppressor neurons, suggesting that they are potentially key targets for therapy
.
”

West deleted a copy of the Arid1b gene in specific brain cells in mice — rather than occurring throughout the body like natural gene loss — to check which circuit changes went awry that could lead to autism-related symptoms such as social impairment, repetitive behavior, learning deficits or anxiety
.
"We knocked out the gene in a subset of cells to study their contribution to circuit abnormalities and observed changes in synaptic properties during development and compared
them to control mice," he said.

In examining the circuit development of brain slices, the researchers found that the loss of genes in excitatory neurons had only a subtle effect on signaling, suggesting that in this mouse model, the loss of genes in excitatory cells was unlikely to be a driver of autism-related behavioral abnormalities
.

However, inhibiting the loss of genes in neurons leads to changes in synaptic physiological functions and connections to varying degrees, depending on their location
in the cortex.

The team also monitored hippocampal activity in the brains of 1-week-old mice lacking a copy of the Arid1b gene in brain cells to see if genetic problems affected the circuitry
at a very early stage.
They found that there was some delay in synapses, involving lower frequency of information transmission in inhibitory neurons, but despite these changes, normal development of the hippocampus appeared to be occurring
.
West said that while it's too early to tell, the finding could have implications
for the potential timing of interventions to repair damaged loops.

A precise understanding of brain circuitry is essential
for designing treatments for autism spectrum disorder.

"Our data suggest that in some cases, circuits between excitatory and suppressor cells seem normal, but circuits next to them consisting of slightly different subtypes of neurons are disrupted — so if you set up inhibition everywhere but inhibition in the wrong place, you could introduce a whole new set of problems
," he said.
That's why what we're doing is valuable, because it can tell us where to target interventions and open up new avenues
for treatment.
”