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Studying Genetic Mutations Linked to Autism Spectrum Disorder

hippocampus neuron with synapses
U of Utah Health neuroscientist Megan E. Williams, PHD, and colleagues studied how genetic changes in mouse neurons like this one located in the hippocampus, a part of involved in learning and memory, could contribute to the development of autism. Photo credit: Megan E. Williams

About one in 54 American children are diagnosed with autism by age 8, according to the Centers for Disease Control & Prevention. Utah’s prevalence rate is even higher, with about one in 50 8-year-old children identified with autism spectrum disorder (ASD). Only New Jersey has a higher rate in the United States.

Some people with this developmental disorder have severe learning disabilities and seem almost totally detached from the surrounding world. Others are less affected, but still display a range of complex neurodevelopmental problems including avoiding physical contact, indulging in repetitive behaviors or have difficulty making social connections.

While there is no cure, scientists suspect ASD is caused, in part, by a host of genetic factors including a defect in a gene called Kirrel3. In a new study, researchers at University of Utah Health recently detected how alterations in this gene could disrupt the formation and function of synapses in the hippocampus, a part of the brain involved in learning and memory. They say a better understanding of this process could eventually lead to medical interventions that reestablish normal synaptic function or help circumvent the problem.

“If a street is closed, you can still get around it by going on a detour,” says Megan E. Williams, PhD, senior author of the study and associate professor of Neurobiology & Anatomy at U of U Health. “The same idea might apply to the circuitry in the hippocampus that is disrupted by alterations in Kirrel3. If we could somehow find ways to bypass that defective circuitry, we might be able to prevent or reduce autistic behaviors in some patients.

The study appears in The Journal of Neuroscience.

Megan Williams, PhD
Megan Williams, PhD

Kirrel3 is one of hundreds of genes suspected of causing ASD and intellectual disability. It produces a protein that is vital for formation of synapses, structures that pass signals between neurons in the brain. In previous research, scientists who disabled or “knocked out” Kirrel3 in laboratory mice found that the rodents developed ASD-like traits including hyperactivity, diminished social interaction and communication difficulties.

“What my team learned from the mice is that if you don’t have the Kirrel3 protein, then you can’t make a very specific kind of synapse in the hippocampus,” Williams says. “It’s like cutting off a leg from a chair. The three other legs are fine, but without the fourth one your balance of activity is completely thrown off.”

Digging deeper, Williams and her lab members sought to unravel how the Kirrel3 protein works in order to better understand its role in ASD. As a starting point, she had one important clue: Kirrel3 proteins help regulate what is called synaptic specificity, a process that only allows a neuron to communicate with other neurons that are compatible with it. So, for instance, neuron A may be able to communicate with neuron B, but not with neuron C.

Based on this, Williams and her colleagues conducted laboratory studies using rodent neurons that were exposed to human Kirrel3 proteins. First, they expressed a normal human Kirrel3 gene in a rodent’s neuron C. This allowed the rodent’s neuron A to synapse with (or communicate) with neuron C, which it normally wouldn’t do. However, when they tried this same approach with mutant versions of Kirrel3 found in patients with ASD, most of the mutant proteins lacked this ability.

“This finding suggests that the mutant versions of Kirrel3 found in patients with ASD do not work properly and is the first experimental evidence that this may in fact be the cause of ASD in those patients,” Williams says. “At the very least, it tells us that Kirrel3 mutations are an important risk factor for ASD and intellectual disabilities. It motivates us to keep studying Kirrel3 to learn more about the cause of these neurodevelopmental disorders.”