Hyperserotonemia ...

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Sticky blood protein yields clues to autism

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 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. "