Researchers at Vanderbilt University Medical Center discovered new links between the prevalent childhood disorder, autism and increased blood serotonin levels.
Serotonin is a chemical having strong links to mood and anxiety and elevated levels of this chemical is also termed as "hyperserotonemia."
AdvertisementThis discovery by Ana Carneiro, Ph.D., and colleagues may have strong implications for the origin of some autism-associated deficits.
The researchers found that a well-known protein found in blood platelets, integrin beta3, physically associates with and regulates the serotonin transporter (SERT), a protein that controls serotonin availability.
Autism is a prevalent childhood disorder, which involves deficits in language, social communication and prominent rigid-compulsive traits. It's been suspected for a long time that Serotonin has an important role in autism as elevated blood serotonin and genetic variations in the SERT have been linked to autism.
Such alterations in brain serotonin have also been linked to anxiety, depression and alcoholism. Antidepressants that block SERT (known as SSRIs, or selective serotonin reuptake inhibitors) block SERT's ability to sweep synapses clean of serotonin.
In the laboratory, the researchers tried to find proteins that interact with SERT that may be responsible for the disorders where serotonin signalling is altered.
"Levels of SERT in the brain are actually quite low, so we decided to see what progress we could make with peripheral cells that have much higher quantities. This took us to platelets," said Randy Blakely, Phd.
She said that in platelets, SERTs accrue serotonin produced in the gut. SSRIs or genetic deletion of SERT in animals prevents serotonin uptake in the platelet.
"Prior research had fingered the integrin beta3 gene as a determinant of blood serotonin levels and, independently, as a risk factor for autism," said Blakely.
The researchers found a large set of proteins that "stick" to SERT in the current study, hoping that they might control SERT activity. And one of these was integrin beta3.
After confirming a physical relationship between the two proteins, the researchers examined if the interaction can change SERT activity. It was found that cells that lack integrin beta3 show reduced serotonin uptake and that integrin beta3 activation or a human integrin beta3 mutation greatly enhances serotonin uptake.
"We found that integrin beta3 can put the serotonin transporter into high gear," said Blakely.
Markedly, Edwin Cook, one of the authors of the study had shown that the same integrin beta3 mutation that elevates SERT activity also predicts elevated blood serotonin.
"Most investigators studying this integrin beta3 mutation have focused on how its high activity state changes platelet clotting and never looked at its impact on serotonin levels or SERT function. Now they have a reason to," explained Carneiro.
"We don't think the platelet itself contributes to autism. But rather we believe that the brain's serotonin transporter may be controlled by integrin proteins in a very similar manner," said Blakely.
The researchers think that increased SERT activity forced by abnormal integrin interactions could limit availability of serotonin in the brain at the time of development, as well as in the adult. This research also may uncover new ways of treating depression.
The study is published in an advance online publication in the Journal of Clinical Investigation.