New research by Vanderbilt University Medical Center investigators provides a physical basis for this phenomenon, which may have profound implications for the origin of some autism-associated deficits.
In an advance online publication in the Journal of Clinical Investigation, Ana Carneiro, Ph.D., and colleagues report 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, a prevalent childhood disorder, involves deficits in language, social communication and prominent rigid-compulsive traits. Serotonin has long been suspected to play a role in autism since elevated blood serotonin and genetic variations in the SERT have been linked to autism.
Alterations in brain serotonin have also been associated with 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.
Working in the lab of Randy Blakely, Ph.D., Carneiro was searching for proteins that interact with SERT that might contribute to disorders where serotonin signaling 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,” said Blakely, the Allan D. Bass Professor of Pharmacology and director of the Vanderbilt Center for Molecular Neuroscience. “This took us to platelets.”
In platelets, SERTs accumulate 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,” Blakely said.
In the current study, Carneiro identified a large set of proteins that “stick” to SERT, presuming they might control SERT activity. One of these turned out to be integrin beta3.
Once they confirmed a physical relationship between the two proteins, Blakely’s team investigated whether the interaction can change SERT activity. They found that cells lacking integrin beta3 exhibit 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. Notably, Edwin Cook, M.D., at the University of Illinois at Chicago and a co-author on 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,” explained Carneiro. “Now they have a reason to.”
“We don’t think the platelet itself contributes to autism,” said Blakely, “but rather we believe that the brain’s serotonin transporter may be controlled by integrin proteins in a very similar manner.”
Carneiro and Blakely believe that too much SERT activity imposed by abnormal integrin interactions could restrict availability of serotonin in the brain during development, as well as in the adult.
“What is even more striking is that this is the second time we have found elevated SERT activity associated with autism,” said Blakely. In a 2005 study, Blakely and Vanderbilt collaborator James Sutcliffe, Ph.D., identified mutations in the SERT gene that triggered elevated SERT activity.
Carneiro is now hot on the trail of integrin interactions with brain SERT as well as engineering mice that express human integrin beta3 mutations.
At a February Keystone Conference, Blakely described preliminary studies with mice that his lab has engineered to express hyperactive SERT mutations. “Together, these new animal models offer an unprecedented opportunity to peel away the complexity of autism and possibly develop new therapies,” he said.
This research also may uncover new ways of treating depression. “Current antidepressant mechanisms still essentially work in the same way they did 25 years ago – by targeting transporter uptake of neurotransmitter directly,” Carneiro said. “Now we may have a completely new way to go about it.”
Craig Boerner | EurekAlert!
Modern genetic sequencing tools give clearer picture of how corals are related
17.08.2017 | University of Washington
The irresistible fragrance of dying vinegar flies
16.08.2017 | Max-Planck-Institut für chemische Ökologie
Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.
As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...
Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.
Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...
For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.
While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...
An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.
The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...
A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.
Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...
16.08.2017 | Event News
04.08.2017 | Event News
26.07.2017 | Event News
17.08.2017 | Physics and Astronomy
17.08.2017 | Earth Sciences
17.08.2017 | Physics and Astronomy