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 this week, 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 David Airey, Ph.D., helped Carneiro and Blakely exploit a separate panel of mice where the SERT GK variant is presented o
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Vanderbilt University Medical Center