With animal models, Tufts neuroscientists break new ground in autism spectrum disorders research

Through the use of animal models, neuroscientists at the Tufts Sackler School of Graduate Biomedical Sciences are breaching new territory in the field of research on autism spectrum disorders (ASD), which could lead to improvements in both medical and therapeutic intervention methods.

Their recent research, which has received most of its funding from the National Institutes of Health (NIH), has shed light on the synaptic causes of ASD and focuses on conditions that are often present, or 'co-morbid,' with ASD, according to Philip Haydon, neuroscience professor and chair of the Department of Neuroscience at the Tufts School of Medicine. The department's research has been using animal models to understand disorders and develop treatments, Haydon said.

“Research in our department focuses on translationally relevant questions," he told the Daily in an email. “We emphasize the use of animal models for disorders of the brain so that we can gain insights into how signals within the brain are modified in such disorders, with the long-term view of providing a foundation for the development of new treatments for neurological and psychiatric disorders.”

Interested in understanding the changes in the developing brain that give rise to behaviors that indicate autism, neuroscience professor Michele Jacob has been using genetically modified mouse models in her lab in order to test different drugs and analyze their effects on behaviors and brain pathways.

“We are comparing what are the behavioral changes we see in the mice, how severe are their learning disabilities, autistic behaviors and seizures, and in different brain regions, we're seeing different molecular pathways malfunctioning,” she said. “We're breaking down what different behaviors or disabilities correlate with those pathways.”

Jonathan Alexander, a Ph.D. student in Jacob’s lab who has been working on Jacob's research for the past five years, explained the way the animal models work.

“We're examining some of the autistic-like behaviors in our mice, and then you can do certain techniques to see what areas of the brain are being activated when they're doing these things,” Alexander said.

These results are then compared to those derived from experiments on a "normal" mouse.

“We're basically studying all of the brain saying okay, now in our model versus a normal mouse, where do these areas light up differently?” Alexander said.

One of the examples Jacob gave is that the mice have been experiencing seizures, which she said is very common in children with autism. She explained that these seizures cause even more developmental delays in the affected children, and that correcting them would be extremely beneficial.

“It's kind of beautiful because the mice are showing a lot of the same types of problems that you would see in people when these pathways don't work properly," she said. “Our goal is to prove that that's a relevant pathway and to test drugs that would potentially correct the problems and maybe improve the behaviors and, significantly, the disabilities.”

In a paper that they published last summer, Alexander and Jacob focused on the adenomatous polyposis coli (APC) mouse model and hypothesized that a molecule other than APC was playing a major role in causing malfunctioning pathways.

“APC itself functions in one of these major pathways and regulates another molecule," Alexander said. "We've been working on the hypothesis that it's not necessarily APC that's causing it, it’s [the other molecule that is] the real central player to these major pathways, it links a lot of different pathways together.”

Alexander expressed hopes to publish an additional paper in the upcoming months with data supporting this hypothesis.

"Basically, [by] not allowing the molecular changes to happen, it turns out that the autistic behaviors are corrected,” he said. “There's been some proof for the principle that treating it with the drugs might help some of the autistic behaviors like repetitive behavior and social interactions.”

Jacob also mentioned that she has been testing to make sure that the drugs have no side effects. She said that she has been collaborating with professors in the School of Engineering to discover whether it's possible to create a culture from human cells in order to test the drugs more quickly.

“At the minimum, [the research] will help us understand what kind of molecular changes in the developing brain lead to disabilities,” Jacob said. “What are the consequences in the brain for how it functions -- how it's connected to other parts."

According to Jacob, a better understanding of these changes and their effects could be used toward therapeutic ends.

"Just knowing that is useful for developing therapeutic strategies, and then we're starting to test [them]; if we can find anything that helps in any way, it would be spectacular," Jacob said.

She noted that of the three drugs they have been testing so far, they are currently focusing on two for which they have encouraging preliminary data.

“There are several different genes [that cause autism], and it may not be that you can treat every single person with one drug,” she said.

Jacob has also been working with Associate Professor of Neuroscience Thomas Biederer to figure out what brain functions correspond with certain autism-relevant behaviors. She explained that the results of this research will indicate which regions of the brain need to be focused on during therapeutic intervention.

Biederer has also been working on the role of certain molecules in synapse development and how they have emerged as a major set of risk factors for ASD. He explained that in his lab, researchers study proteins that control and hold synapses together.

“In this larger group of synaptic adhesion proteins, there are several proteins in that family that have been linked through human genetic studies to ASD," he said. "And so, by studying how these proteins control synapse formation and how they signal in synapse formation, we will have an entry point to understand that aspect of ASD.”

With the long-term goal of understanding and treating ASD, Biederer has employed approaches from different disciplines, including chemistry, proteomics and cell cultures. He noted that the use of genetically-modified mouse models has been the most beneficial.

"My lab can demonstrate that these transsynaptic interactions can draw us information of new synapses, and we can also show that these proteins regulate the ability of synapses to reorganize in an activity kind of manner, and this ultimately can be used to manipulate the ability of animals to learn,” he said. “So that ultimately, we have been able to make animal models that can learn better."

He emphasized the importance of this research in its transferability to humans, as the research is showing that these processes can be used to improve learning and memory.

"We are helping to understand what the functions of these proteins are in normal brain development, and with that we can understand what effects these mutations have," he said. "Synaptic aberrations are one of the most important factors in developing autism, and my lab's research helps to understand how these synaptic aberrations arise from molecular changes."

Biederer estimated between 200 and 800 risk factors for ASD in the human genome, explaining that it is extremely rare that a case of ASD would arise from only one mutation.

"That means most patients who have autism are different from each other; there's not one autism because you have different combinations of different risk factors,” he said. “What is important, though, is if you analyze these risk factors, that patterns emerge, and one of the important patterns is changes in synapse mutations and synapse-organizing proteins."

Through his research, Biederer hopes to develop a more precise subdivision of ASD in order to refine therapeutic interventions.

"This type of sub-classifying autistic children will actually help tremendously when it comes to developing therapeutic intervention,” he said. “Having these molecular tools of subdividing autism into sub-types of autism will actually ... advance our molecular understanding and open up molecular intervention for these subtypes and then accelerate treatment."