Mouse Model explores Role of Serotonin in Autism

Mouse Model explores Serotonin and Autism

Jeremy Veenstra-VanderWeele (left) and Randy Blakely pose at the entrance to the Vanderbilt Laboratory for Neurobehavior, where their studies in mice have revealed a clue to autism.

Vanderbilt University researchers are using mice to explore how altered brain serotonin levels during development may produce long-lasting changes in behavior and impact the risk for autism.

Serotonin is known for giving a sense of well-being and happiness. It is a neurotransmitter, a chemical that acts like a radio tower in the brain conveying signals among cells called neurons.

An earlier study at the Graduate School of Biomedical Sciences explored the role that serotonin plays in autism spectrum disorders. Dr. Georgianna Gould and colleagues showed that a medication called buspirone improved the social behaviors of mice.  Some genetic variations result in diminished transmission of serotonin between neurons. Buspirone increased transmission by partially mimicking the effects of serotonin at cellular sites called receptors.

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 the researchers detail the creation of a mouse model with a small biochemical change that 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, Schain and Freedman reported that about 40% of children with autism are born with high circulating blood levels of serotonin. This finding has been repeated many times by other researchers.  Despite around 600 published research papers looking at autism and serotonin, researchers have been largely puzzled by this – until now.

In the current study, Veenstra-VanderWeele, Blakely and their colleagues showed that they could produce elevated blood levels of serotonin, “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.

This is one more potential factor in understanding the causes of autism. Experts believe the wide spectrum of autistic behaviors represents a complex web of interactions between many genes and environmental factors.

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