Novel Mouse Model sheds new Light on Autism Spectrum Disorder

A new mouse model is the first to show that when more of acetyl-CoA moves between different parts of nerve cells in the mouse brain, it can lead to behaviors that resembles some aspects of autism spectrum disorder (ASD) in humans. Acetyl-CoA, is a major part of the process cells use to make energy from food. It’s also used within cells to tag different proteins, which influences where and how they function. Local concentrations of acetyl-CoA and its movement, or flux, between different areas within cells is tightly regulated.

“We show, for the very first time, that changes in acetyl-CoA flux, and not just changes in its levels, in individual neurons can affect neuronal activity,” says Prof Luigi Puglielli, UW-Madison School of Medicine and Public Health and the UW’s Waisman Center.

The researchers engineered mice to make the human version of a protein that ferries acetyl-CoA into a specific compartment within cells. Previous studies revealed that mutations in this ferrying protein, called AT-1, are associated with spastic paraplegia, severe developmental delays and ASD in humans. But how mutations in AT-1 are linked to these developmental disorders was unknown. The current study showed that when AT-1 levels are high, as is the case in the brains of the mice with the human AT-1 protein, increased movement of acetyl-CoA into specific areas within cells sets off a chain reaction of consequences that the researchers think ultimately leads to the mice showing autism-like behaviors. “We could call AT-1 a ‘master regulator’ of intracellular acetyl-CoA flux, which, in turn, can be said to be a master regulator of essential neuronal functions,” says Puglielli.

In the brains of mice with human AT-1, atypical localization of acetyl-CoA in the nerve cells causes a slew of more than 400 genes to become dysregulated and pump out higher levels of proteins. Several of these proteins play important roles in regulating both the growth of neurons and how nerve impulses travel through them. The global changes in protein levels caused by manipulating these master regulators leads to significant changes in what nerve cells look like and how they function in these mice. Eg. the ends of the nerve cells become more branched and spiny and their ability to mediate typical learning and memory formation is compromised.

Changes in how the nerve cells look and function caused the AT-1 mice to behave atypically, in ways that resemble aspects of ASD in humans. “We need to be able to modify genetic, molecular and biochemical aspects of the disorder,” says Puglielli. They are now looking at other proteins that regulate acetyl-CoA movement within cells. “Mutations in these proteins are also associated with different disorders, including ASD and intellectual disability,” he says. http://news.wisc.edu/novel-mouse-model-sheds-new-light-on-autism-spectrum-disorder/