The hunt for the disrupted brain signals behind autism

Part of understanding the underlying causes of autism spectrum disorders relies on determining which signaling patterns of cells in the brain are disrupted and when, during nervous system development, the disruption occurs.

New research results from mouse models of genetic risk for autism support the idea that the loss of a specific gene interferes with brain cells whose role is to inhibit signaling. Although there are fewer of these cells than other neurons and their signals do not travel very far, they have a huge influence on the patterns of information transmission in the brain and to the rest of the body.

Jason Wester

Researchers at Ohio State University found that deleting one copy of the autism risk gene Arid1b from specific brain cells decreased the number of inhibitory cells and reduced signaling between inhibitory cells and the excitatory cells they help control. Previous research has suggested that reduced inhibitory signals in mouse models of the disorder drive a range of autism-related behaviors.

In separate experiments, scientists found that signaling changes related to inhibitory cells can be seen in the same genetic mouse models of autism spectrum disorder (ASD) very soon after birth, but the disruption might not be strong enough to interfere with normal brain development. by a host of other genes.

Studying the effects of disease risk genes on brain circuitry is intended to pave the way for possible therapies, but this pursuit also offers insight into normal circuitry functioning because “in many cases it is still a mystery,” said lead author Jason Wester, assistant professor. of Neuroscience at Ohio State’s College of Medicine.

“Circuits are the level of analysis that is crucial to understanding how the brain works – it’s a key to understanding not only what’s wrong with neurodevelopmental disorders, but also understanding how normal circuits work” , Wester said. “We ask what neurodevelopmental disorders can tell us about how normal circuits work – and what that tells us about how we try to fix disturbed circuits.”

The research posters were presented today (Monday, November 14, 2022) at Neuroscience 2022, the annual meeting of the Society for Neuroscience.

There are many genes associated with the risk of ASD, which is one of the reasons it is such a difficult disorder to study and treat. In fact, in a recent data-mining RNA sequencing study, Wester’s lab created the first curated list of genes linked to the formation of synapses – vehicles for transmitting circuits between cells – through the brain.

“We were hoping to provide clues as to whether or not we might be looking at therapies for autism that might be repairable throughout the brain if we changed a single gene,” he said. “Unfortunately, we found that was not likely. Autism risk genes are not concentrated in one specific group. But we found many of them among inhibitory neurons, suggesting that they are potentially key targets for therapeutics.

Wester deletes a copy of the Arid1b gene in specific brain cells in mice – rather than throughout the body the way natural gene loss would occur – to examine where circuitry changes occur in a way that leads to associated symptoms to autism, such as problems with social communication, repetitive behaviors, learning deficits or anxiety.

“We delete the gene in a subpopulation of cells to study their contributions to circuit abnormalities, and examine changes in synaptic properties during development over time and compare them to control mice,” he said. he declares.

When examining the development of circuits in brain slices, the researchers found that the loss of the excitatory neuron gene had only subtle effects on signaling, suggesting, in this mouse model, that the loss gene in excitatory cells is not a likely driver of autism. – related behavioral abnormalities.

Loss of the gene in inhibitory neurons, however, led to changes in synaptic physiological functions and connectivity at varying levels depending on their location in the cortex.

The team also monitored hippocampal activity in the brains of week-old mice that lacked a copy of the Arid1b gene in brain cells to see if genetic issues were affecting circuitry at this very early stage. They found delays in synapse development and a lower frequency of information transmission involving inhibitory neurons, but normal hippocampal development appears to occur despite these changes. Although it’s too early to tell, this discovery could have implications for the potential timing of interventions related to the repair of damaged circuitry, Wester said.

Accuracy in understanding brain circuitry is critical to designing therapies to treat ASD.

“Our data indicates that in some cases the circuits between excitatory and inhibitory cells appear normal, but the circuits right next to them made up of slightly different neuron subtypes are the ones that are disrupted – so if you dial the inhibition everywhere and dial it in the wrong places, 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 therapies.”

This work was supported by a pilot award from the Simons Foundation Autism Research Initiative (SFARI).

Poster co-authors include Alec Marshall, Danielle Boyle, Meretta Hanson, Devipriyanka Nagarajan, Julie Fitzgerald, Emilee Gaitten, Noor Bibi, Olga Kokiko-Cochran, and Bin Gu, all from Ohio State.

#hunt #disrupted #brain #signals #autism

Leave a Comment

Your email address will not be published. Required fields are marked *