Wiring the Brain to Learn Requires Autism-Linked Gene

Rumbaugh lab found that the gene Syngap1 enables normally quiet neurons to spring into activity during sensory challenges, while other neurons are quieted.

Study Finds Imbalance Between Active and Inactive Neurons if Syngap1 Diminishes, Resulting in Reduced Connections and Learning Impairment

The brain constantly rewires itself with experience. We learn to babble and speak because our parents spoke to us first. We know how to ride a bike because we kept trying until something clicked. Scientists refer to this process of constant learning as “experience-dependent brain plasticity.” A new study from Scripps Research neuroscientist Gavin Rumbaugh, PhD, finds autism risk gene Syngap1 acts as a critical controller of it.

In whisker-challenge studies in healthy mice, the team found that Syngap1 enables normally quiet neurons to spring into activity, strengthening connections to other neurons. Partial loss of Syngap1 leads to impaired learning and thinking, the scientists report in the journal Proceedings of the National Academy of Sciences on Aug. 25.

“During a new experience, some neurons will increase their activity, and some will decrease their activity,” Rumbaugh explains. “In the Syngap1 mouse models, we see imbalanced changes across these neurons, which may be a process that underlies deficits in learning and behavior.” 

The brain works as an interconnected network of cells. Groups of neurons that act together to control behavior and learning are referred to as ensembles. Understanding how genes control ensembles has been limited, in part, by a lack of tools to study them, until recently, Rumbaugh says.

“Behavior is driven by groups of neurons that fire together. Before, we would look at neurons frozen in time, a snapshot,” Rumbaugh says. “Now we can look at the dynamics of hundreds of neurons in real time as an animal gains new experience. It’s a game-changer.” 

Using a two-photon microscope and equipment that measures neural activity, the scientists tracked changes to a neural ensemble in the mouse cortex that is activated by a sensory experience. First, they measured it after a period of sensory deprivation. Next, they removed some whiskers on one side of the mouse’s face, which led to a unique sensory experience within the same environment, and then measured the activity again weeks later, documenting how neurons in their brains rewired to adapt to the challenge. They carried out these experiments both in “wild-type” neurotypical mice, and in Syngap1 mice, those bred to have one non-functioning copy of the autism risk gene. Loss of both Syngap1 copies is lethal.

The methods are enabling fascinating new insights about the brain and how it’s wired. One 2012 mouse study found that neural ensembles don’t uniformly change in response to a new sensory experience. Some neurons are inherently quiet during sensory experience, some are moderately active, and a much smaller subset of neurons are extremely active. During learning, the quiet and busy neurons switch roles. Active neurons became quiet, while quiet ones fired much more, in the process, building new brain circuits, the team from the Brain Research Institute at the University of Zurich in Switzerland found.

Rumbaugh’s team found similar results in neurotypical mice after their whisker experiments. However, in the Syngap1 deficient mice, not only did the quiet neurons fail to activate after new experience, their other neurons, the highly active ones that dampen their activity, operated as usual. The combined effect was dramatic. It was apparent that Syngap1 is needed to strengthen connectivity specifically in the normally quiet neurons, Rumbaugh says.

“What we think is happening is, you are taking away the strengthening mechanism in the Syngap mice, but the weakening mechanism is normal. So, you have a net weakening of the neural ensemble during this type of experience, which you can imagine is very bad for learning new things,” Rumbaugh says.

Children born with only one working copy of the Syngap1 gene experience a host of developmental issues including autistic behaviors, sensory processing challenges, speech impairment, seizures, and severe intellectual disability.

Syngap1 mutations are considered rare, about 1 percent of all causes of autism, but recent studies have estimated true numbers may be considerably higher, since families only learn of their child’s Syngap1 status after missed milestones and genetic tests.

The study sheds light on the mechanism underlying serious learning and thinking disabilities in children with Syngap1 mutations. It also sheds light on the genetic underpinnings of experience-dependent brain plasticity for everyone, Rumbaugh notes.

“We found that having only one working copy of Syngap1 impacts the plasticity of low-activity neurons, but it doesn’t impact plasticity in high-activity neurons, suggesting other genes must do this. Together, many genes must act together to efficiently redistribute activity throughout neurons in our brains as we learn,” Rumbaugh adds.

The study also raises the question, could increasing Syngap1 expression improve thinking and learning, and improve the lives of these children and their families?

“I am on a quest to understand why these Syngap1 kids have such poor cognitive function,” Rumbaugh says. “Syngap needs to be in the brain to strengthen neurons during learning. We are looking to create medications to increase Syngap expression to help these kids. Given our results, we also suspect that increasing Syngap expression may generally improve learning by boosting connections in the brain.” 

In addition to Rumbaugh, the authors of, Syngap1 regulates experience-dependent cortical ensemble plasticity by promoting in vivo excitatory synapse strengthening,” are Nerea Llamosas, Sheldon D. Michaelson, Thomas Vaissiere, Camilo Rojas and Courtney A. Miller, all of Scripps Research in Jupiter, Florida.

Funding for this study was provided by the National Institutes of Health, MH096847, MH108408, NS064079, and NS 110397. Llamosas was supported by a postdoctoral training fellowship from the SynGAP Research Fund.