Many children with autism have elevated blood levels of serotonin – a chemical with strong links to mood and anxiety. But what relevance this “hyperserotonemia” has for autism has remained a mystery.
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.”
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.”
After the first few chapters, and reading about the behaviors and capabilities of Temple, I wondered if anyone had researched serotonin reuptake inhibitors in Autistic children.
This may seem like a strange thought to cross anyone's mind, especially as I'm a computer geek.
However, 12 years ago, due to a stroke, I inherited (for a great 6 months) some of the traits Temple mentioned.
I'm ADHD prime - unable to focus on anything - except computers - where, I exhibited hyperfocus - I was just lucky that it was a marketable skill. I cant easily recall numbers, have no visual thoughts, I still cannot navigate my own home town without a GPS. I cannot remember 4 numbers, its impossible for me to hear a telephone number and then dial it. I have trouble recognizing my own family's faces in a crowded restaurant (all this was pre stroke - and continues).
I was having panic attacks after the stroke (I lost speech and the ability to spell) - I also had to tour Asia - and have daily blood tests in very strange places (Hong Kong, Singapore, Australia) as i was still on Coumadin and needed PT/INR tests.
A doctor suggested I try Serzone - the effect was unbelievable, suddenly I could recall anything, read whole lists of telephone numbers and reread them from my mind, I was a genius. There were side effects - I developed a very high sensitivity to light (had to wear sunglasses even at dinner time), needed quiet (which was shocking because as ADD - I like to have the TV, radio, computer all going at one time, I needed noise to focus) I could obsess over something for hours (luckily it was computer issues - so no one minded). I developed a hatred for social gatherings, became disconnected from my family, lost my sense of humor.
I was taken off of Serzone (it appears people were dying - I felt at that time that I was willing to take the risk - just to keep my super memory).
i was completely unsurprised to read over the last two nights that high levels of Serotonin have been associated with some people on the Autism Spectrum (I apologize if I'm using the wrong terminology).
Much seems to have been written about Serotonin levels - Serzone - from what I've read is a Serotonin–norepinephrine–dopamine reuptake inhibitor - looking back - I would not want that hyperfocus and genius memory at the expense of what it did to my social life.
I suppose - where I'm going with this - is - possibly - easier to induce temporary Autistic like symptoms in someone with ADD - who can articulate the effects of the drugs - and - work backwards - something in the Serzone changed my personality (interestingly it didn't stop the panic attacks, but i lied to the doctor so i could keep taking it).
My heart goes out to all parents with Autistic children - I sincerely hope this Movie gives the Autism movement the boost and focus among the general population it needs to find was to moderate these awful socially isolating traits
.