Immune p38-alpha MAPK activation: Convergent mechanism linking autism models

  • Awarded: 2014
  • Award Type: Targeted: Innate Immune System
  • Award #: 323427

Autism appears to be caused by a complex interplay of genetic and environmental factors. Over the past decade, scientists have established multiple animal models of autism using both genetic and environmental manipulations, demonstrating the presence of communication and social behavior deficits in these animals, as well as the presence of repetitive behaviors characteristic of individuals with autism. Randy Blakely and his colleagues at Vanderbilt University in Nashville, Tennessee, believe that the activation of a class of enzymes known as p38-alpha MAP kinases (p38-alpha MAPK) may underlie the ability of both genetic and environmental factors to produce autism.

Blakely’s efforts in autism research began with the 2005 discovery of multiple rare genetic mutations in individuals with autism that alter the structure of the serotonin transporter, or SERT, protein. SERT is known to many as the brain’s major target for antidepressant medications such as Prozac. Blakely and his team reported the cloning of the human SERT gene in 1993 and, a few years later, demonstrated that SERT is expressed early in brain development, where it could contribute to developmental disorders such as autism.

In a search for regulators of SERT, Blakely’s team identified p38-alpha MAPK, a gene known to play critical roles in immune system function, including those arising as a consequence of either maternal or neonatal infection. What’s more, a genetic mouse model Blakely produced to express the most common of the SERT mutations he found in individuals with autism displays not only behavioral features reminiscent of autism but also inappropriate regulation of SERT by p38-alpha MAPK.

These findings drive Blakely’s efforts to determine whether p38-alpha MAPK signaling is a key link in how SERT and serotonin control brain development and can link immune system activation to features of autism, as well as be targeted by new autism drugs.

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