New Role For Serotonin 'Ironed Out'

[Guest guest]

>New Role For Serotonin 'Ironed Out'

>ScienceDaily (Jan. 29, 2009) —

>http://www.sciencedaily.com/releases/2009/01/090127123009.htm

>

>Vanderbilt University Medical Center investigators have found a

>surprising link between brain iron levels and serotonin, a

>neurotransmitter involved in neuropsychiatric conditions ranging from

>autism to major depression.

>

>Appearing in the Proceedings of the National Academy of Sciences the

>week of January 27, the study by Randy Blakely, Ph.D., and colleagues

>also demonstrates the utility of a powerful in silico approach for

>discovering novel traits linked to subtle genetic variation.

>

>The serotonin transporter protein (SERT) regulates serotonin

>availability in the brain and periphery, and variations in human SERT

>have been linked to many neurobehavioral disorders – including

>alcoholism, depression, autism and obsessive-compulsive disorder. SERT

>is also a major target for medications like the selective serotonin

>reuptake inhibitors (SSRI) used for treating depression.

>

>Thanks to a serendipitous mix-up in an animal order, Blakely and

>first author Ana Carnerio, Ph.D., discovered that a mouse strain they

>had been using to studying SERT function – called C57BL/6 –

>actually carries a mutation that reduces the function of the

>transporter.

>

> " Importantly, low-functioning variants of human SERT have been

>associated with anxiety, depression, and reduced efficacy of SSRI

>medications, " notes Blakely, senior author and director of the

>Vanderbilt Center for Molecular Neuroscience.

>

>By querying an online resource called the Mouse Phenome Database,

>they found that most mouse strains possess a SERT version called " ER "

>– which is identical to the sequence found in human SERT. A small

>number of strains, however, including the commonly studied C57BL/6

>strain, carry a different version (called " GK " ).

>

>Carneiro realized that she could utilize her identification of SERT

>GK to elucidate new aspects of brain chemistry and behavior.

>Vanderbilt collaborator Airey, Ph.D., helped Carneiro and

>Blakely exploit a separate panel of mice where the SERT GK variant is

>presented on many different genetic backgrounds – a so-called

> " recombinant inbred " population termed BXD mice.

>

>Using lines from this population, the team found that SERT GK mice

>performed differently than SERT ER mice on tests of anxiety and

>depression, consistent with reduced function of SERT GK. Importantly,

>a public database of anatomical, biochemical and behavioral features

>exists for all mice in the BXD population, allowing Blakely and

>colleagues to identify novel traits linked with the low functioning

>SERT. From this in silico approach, Blakely and colleagues identified

>multiple trait differences affected by the SERT GK/ER variation,

>including traits associated with alcohol consumption and brain

>dopamine signaling.

>

>Additionally, they found that iron levels in the brains of mice with

>the GK variant were significantly higher than in the ER variant mice.

>Iron is required to synthesize both serotonin and dopamine, and

>serotonin receptors are known to regulate iron-carrying proteins. But

>SERT had not been previously shown to control brain iron levels.

>Follow-up studies with mice where the SERT gene was eliminated (SERT

> " knock-out " mice) verified a critical role for the transporter in

>controlling brain iron levels.

>

> " Because SERT is such an important drug target in treating anxiety,

>depression and OCD, we need to stop and think about how iron might be

>influencing these disorders, " Blakely said. The study also

>demonstrates the power of an in silico approach – combined with

>traditional experimentation – in understanding how genes affect

>complex traits.

>

> " The broader number of findings in our paper derives not from

>(experiments) we did, but from what the (scientific) community

>collectively did to populate the BXD database, " Blakely noted.

>

> " Indeed, this is a great example of how biostatistical approaches can

>help limit the amount of experimentation that is needed with animals. "

>

>Other authors included Brent and Chong-Bin Zhu, M.D., Ph.D.,

>from Vanderbilt, and researchers from Nantong University, the

>University of Tennessee Heath Science Center, Oak Ridge National

>Laboratory and the University of North Carolina at Greensboro. The

>research was supported by the National Institutes of Health.

>

>Blakely is also the Allan D. Bass Professor of Pharmacology and a

>professor of Pharmacology and of Psychiatry.

>

>

>

>

>

>

>