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Novel mouse model for autism yields clues to a 50-year-old mystery

Date:
March 20, 2012
Source:
Vanderbilt University Medical Center
Summary:
Early disruptions in serotonin signaling in the brain may contribute to autism spectrum disorder (ASD), and other "enduring effects on behavior," researchers report. The investigators previously identified genetic variations in children with ASD that disrupt the function of the serotonin transporter, which regulates the supply of serotonin. Now, they report the creation of a mouse model that expresses the most common of these variations.

Illustration. Early disruptions in serotonin signaling in the brain may contribute to autism spectrum disorder (ASD), and other "enduring effects on behavior," Vanderbilt University researchers report.
Credit: nobeastsofierce / Fotolia

Early disruptions in serotonin signaling in the brain may contribute to autism spectrum disorder (ASD), and other "enduring effects on behavior," Vanderbilt University researchers report.

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Serotonin is a brain chemical that carries signals across the synapse, or gap between nerve cells. The supply of serotonin is regulated by the serotonin transporter (SERT). In 2005, a team of Vanderbilt researchers led by Randy Blakely and James Sutcliffe identified rare genetic variations in children with ASD that disrupt SERT function.

In a new study published this week in the Proceedings of the National Academy of Sciences (PNAS), the researchers report the creation of a mouse model that expressed the most common of these variations.

The change is a very small one in biochemical terms, yet it appears to cause SERT in the brain to go into overdrive and restrict the availability of serotonin at synapses.

"The SERT protein in the brain of our mice appears to exhibit the exaggerated function and lack of regulation we saw using cell models," said Blakely, director of the Vanderbilt Silvio O. Conte Center for Neuroscience Research.

"Remarkably, these mice show changes in social behavior and communication from early life that may parallel aspects of ASD," noted first author Jeremy Veenstra-VanderWeele, assistant professor of psychiatry, pediatrics and pharmacology.

The researchers conclude that a lack of serotonin during development may lead to long-standing changes in the way the brain is wired.

In 1961, investigators at Yale discovered that as many as 30 percent of children with autism have elevated blood levels of serotonin, a finding described as "hyperserotonemia."

Since then, these findings have been replicated many times. Indeed, hyperserotonemia is the most consistently reported biochemical finding in autism, and is a highly inherited trait. Yet, the cause or significance of this bio-marker has remained shrouded in mystery.

Until now. In the current study, Veenstra-VanderWeele, Blakely and their colleagues showed that they could produce hyperserotonemia in mice that express a variant of a human SERT gene associated with autism.

Because the genetic change makes the transporter more active, higher levels of serotonin accumulate in platelets and therefore in the bloodstream. In the brain, overactive transporters should have the opposite effect -- lowering serotonin levels at the synapse and producing behavioral changes relevant to autism. That's exactly what the researchers observed.

Of course, no mouse model can completely explain or reproduce the human condition. Neither does a single genetic variation cause autism. Experts believe the wide spectrum of autistic behaviors represents a complex web of interactions between many genes and environmental factors.

But animal models are critical to exploring more deeply the basis for the developmental changes that are observed in ASD. The scientists are using these mice to explore how altered brain serotonin levels during development may produce long-lasting changes in behavior and impact the risk for autism.

Scientists from the National Institute of Mental Health, the Medical University of South Carolina and the University of Texas Health Science Center at San Antonio contributed to the study.

The research was supported by the National Institutes of Health, the advocacy organization Autism Speaks and the American Academy of Child and Adolescent Psychiatry.


Story Source:

The above story is based on materials provided by Vanderbilt University Medical Center. Note: Materials may be edited for content and length.


Journal Reference:

  1. J. Veenstra-VanderWeele, C. L. Muller, H. Iwamoto, J. E. Sauer, W. A. Owens, C. R. Shah, J. Cohen, P. Mannangatti, T. Jessen, B. J. Thompson, R. Ye, T. M. Kerr, A. M. Carneiro, J. N. Crawley, E. Sanders-Bush, D. G. McMahon, S. Ramamoorthy, L. C. Daws, J. S. Sutcliffe, R. D. Blakely. Autism gene variant causes hyperserotonemia, serotonin receptor hypersensitivity, social impairment and repetitive behavior. Proceedings of the National Academy of Sciences, 2012; DOI: 10.1073/pnas.1112345109

Cite This Page:

Vanderbilt University Medical Center. "Novel mouse model for autism yields clues to a 50-year-old mystery." ScienceDaily. ScienceDaily, 20 March 2012. <www.sciencedaily.com/releases/2012/03/120320115625.htm>.
Vanderbilt University Medical Center. (2012, March 20). Novel mouse model for autism yields clues to a 50-year-old mystery. ScienceDaily. Retrieved October 24, 2014 from www.sciencedaily.com/releases/2012/03/120320115625.htm
Vanderbilt University Medical Center. "Novel mouse model for autism yields clues to a 50-year-old mystery." ScienceDaily. www.sciencedaily.com/releases/2012/03/120320115625.htm (accessed October 24, 2014).

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