Some of autism’s symptoms may stem from malfunctioning communication between cells in the brain due to having more synapses than necessary, new research with mice suggests.
“You might think that having more synapses would make the brain work better, but that doesn’t seem to be the case.”
Researchers found that a defective gene linked to autism influences how neurons in the brain connect and communicate with each other. Rodents that lack this gene form too many connections between brain neurons and have difficulty learning.
“This study raises the possibility that there may be too many synapses in the brains of patients with autism,” says senior author Azad Bonni, a professor of neuroscience and head of the neuroscience department at the Washington University School of Medicine in St. Louis.
“You might think that having more synapses would make the brain work better, but that doesn’t seem to be the case. An increased number of synapses creates miscommunication among neurons in the developing brain that correlates with impairments in learning, although we don’t know how,” Bonni says.
Understanding ubiquitin
Autism is a neurodevelopmental disorder affecting about one out of every 68 children characterized by social and communication challenges.
Among the many genes linked to autism in people are six genes that attach a molecular tag, called ubiquitin, to proteins. These genes, called ubiquitin ligases, function like a work order, telling the rest of the cell how to deal with the tagged proteins: This one should be discarded, that one should be rerouted to another part of the cell, a third needs to have its activity dialed up or down.
People with autism may carry a mutation that prevents one of their ubiquitin genes from working properly. But how problems with tagging proteins affect how the brain is hardwired and operates, and why such problems may lead to autism, has remained poorly understood.
To understand the role of ubiquitin genes in brain development, Bonni, first author Pamela Valnegri, and colleagues removed the ubiquitin gene RNF8 in neurons in the cerebellum of young mice. The cerebellum is one of the key brain regions affected by autism.
The researchers found that neurons that lacked the RNF8 protein formed about 50 percent more synapses—the connections that allow neurons to send signals from one to another—than those with the gene. And the extra synapses worked.
By measuring the electrical signal in the receiving cells, the researchers found that the strength of the signal was doubled in the mice that lacked the protein.
The cerebellum’s role
The cerebellum is indispensable for movement and learning motor skills such as how to ride a bicycle. Some of the recognizable symptoms of autism—such as motor incoordination and a tendency to walk tippy-toed—involve control of movement.
The animals missing the RNF8 gene in the neurons of their cerebellum did not have any obvious problems with movement: They walked normally and appeared coordinated. When the researchers tested their ability to learn motor skills, however, the mice without RNF8 failed miserably.
Eye motions could flag certain elements of autism
The researchers trained the mice to associate a quick puff of air to the eye with the blinking of a light. Most mice learn to shut their eyes when they see the light blink, to avoid the irritation of the coming air puff. After a week of training, mice with a functioning copy of the gene closed their eyes in anticipation more than three quarters of the time, while mice without the gene shut their eyes just a third of the time.
While it is best known for its role in movement, the cerebellum is also important in higher cognitive functions such as language and attention, both of which are affected in autism. People with autism often have language delays and pay unusually intense attention to objects or topics that interest them. The cerebellum may be involved not only in motor learning but in other features of autism as well, the researchers say.
What’s next?
Of course, there is a world of difference between a mouse that can’t learn to shut its eyes and a person with autism who struggles to communicate. But the researchers say the findings suggest that changing how many connections neurons make with each other can have important implications for behavior.
Since this paper was written, Bonni and colleagues have tested the other autism-associated ubiquitin genes. Inhibition of all genes tested cause an increase in the number of synapses in the cerebellum.
“It’s possible that excessive connections between neurons contribute to autism,” Bonni says. “More work needs to be done to verify this hypothesis in people, but if that turns out to be true, then you can start looking at ways of controlling the number of synapses. It could potentially benefit not just people who have these rare mutations in ubiquitin genes but other patients with autism.”
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The researchers report their findings in the journal Nature Communications.
A National Institutes of Health (NIH) grant, the Mathers Foundation, and a European Molecular Biology Organization grant supported this study.
