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Study further links immune response, serotonin signaling

Nov. 5, 2015, 8:43 AM

Vanderbilt University scientists are a step closer to understanding how inflammation in the body can affect mood and behavior.

Their latest discovery, reported this week in the journal Translational Psychiatry, provides further evidence that a signaling pathway involved in the body’s immune response to infection and other stressors can regulate the brain’s control of the neurotransmitter serotonin.

Randy Blakely, Ph.D.

“The inflammatory pathway that we have identified is likely one by which serotonin signaling is regulated in general,” said Randy Blakely, Ph.D., who led the research team. “By targeting this pathway, we might come up with better medications to treat disorders where manipulation of serotonin signaling has proved beneficial, as in depression.”

For the better part of a decade, Blakely and his colleagues have investigated the p38alpha MAPK signaling pathway. MAPKs, or mitogen-activated protein kinases, are enzymes that regulate the body’s response to infection and other stress stimuli, among other roles.

The latest findings add to an increasing body of evidence that the p38alpha MAPK pathway links the body’s immune response to regulation of the brain serotonin transporter. The transporter, which eliminates serotonin from the synapse, or gap between nerve cells, is the target for a major class of anti-depressants.

Selective serotonin reuptake inhibitors or SSRIs like Prozac increase the brain’s supply of serotonin by blocking the transporter. But it can take weeks to achieve a therapeutic effect, and not everyone responds to them.

Using genetic mouse models they developed, Blakely and his colleagues showed that the MAPK pathway acts in serotonin neurons to communicate signs of infection in the periphery. That leads to an elevation in serotonin transporter activity and multiple serotonin-linked behaviors.

“The net consequence of p38alpha MAPK activation is … we get elevated transporter activity that can drain away the serotonin,” said Blakely, the Allan D. Bass Professor of Pharmacology and Psychiatry.

The impact on behavior was profound. When an inflammatory response was produced by peripheral injection of a piece of bacteria in mice, their serotonin neurons showed rapid activation of the p38alpha MAPK pathway. The animals also exhibited depressive-like behaviors, including signs of heightened anxiety and despair.

But when, in the current study, the p38alpha MAPK pathway was genetically “knocked out,” specifically in serotonin neurons, these behaviors were extinguished. The inflammatory agent had no effect. The animals were, as Blakely described them, “resilient.”

This “is a response to an acute inflammatory agent,” Blakely cautioned. It says nothing about what may occur in chronic inflammatory states. “That’s something we’re eager to pursue with the same kind of genetic approach,” he said.

At the same time, “I doubt that (this MAPK pathway) has evolved only to respond to inflammation,” he said.

Since the p38alpha MAPK pathway has the ability to turn up and turn down the activity of the serotonin transporter, “maybe if we targeted the way (it) regulates the transporter as opposed to blocking the transporter itself, we might have a better antidepressant,” Blakely said.

Blakely is director of the Vanderbilt/NIMH Silvio O. Conte Center for Neuroscience Research, which is supported by the National Institute of Mental Health, part of the National Institutes of Health (NIH). First author of the study was Nicole Baganz, Ph.D., a postdoctoral fellow in the Blakely lab.

The research was supported in part by NIH grants NS007491, MH094527 and MH096972, the Brain and Behavioral Research Foundation and the Institute for Psychiatric Neuroscience.

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