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Possible Cause of Postpartum Depression Pinpointed
Date:7/30/2008

Mouse study implicates GABA receptors in the central nervous system

WEDNESDAY, July 30 (HealthDay News) -- Researchers have uncovered a potential cause for postpartum depression, at least in mice.

According to the study, from assistant researcher Jamie Maguire and lead researcher Istvan Mody, both of the David Geffen School of Medicine at the University of California, Los Angeles, dysregulation of a particular class of proteins called GABA receptors on the surface of certain neurons in the brain may induce post-delivery mood disorders ranging from "baby blues" to postpartum psychosis.

The findings immediately suggest a possible therapeutic intervention, the authors noted. They also provided researchers with a new animal model for studying the biology and treatment of the disease -- a valuable research tool that could accelerate the development of new treatments.

Yet the work was not performed in humans, stressed Dr. Bernard Carroll, scientific director of the Pacific Behavioral Research Foundation in California. Just because these animals appear to suffer from a disease akin to postpartum depression, he said, does not mean the two conditions are identical.

"We have to remember that the model is not the disease," he said.

The results were published in the July 31 issue of Neuron.

The protein at the heart of this study, the GABA receptor (type A), serves an inhibitory role in the nervous system, dampening the effect of excitatory neurotransmitters in response to its substrate, GABA. These receptors can bind to more than one molecule, however, and one particular class of molecules called neurosteroids can modulate the receptors' activity.

Neurosteroids are produced in the central nervous system from steroid hormones such as progesterone. During pregnancy, the levels of reproductive hormones (including progesterone) rise sharply, only to drop to pre-pregnancy levels shortly after delivery. As a result, neurosteroid levels also rise and fall.

Maguire and Mody wanted to see what happens to GABA receptors in the brains of mice undergoing the hormonal swings associated with pregnancy. By comparing virgin, pregnant and postpartum mice, the pair discovered that GABA receptor abundance (and function) falls during pregnancy and then returns to pre-pregnancy levels following birth.

That makes sense from a homeostatic point of view, Maguire explained. For the body to maintain a constant level of GABA receptor-derived inhibition, receptor abundance must stay more or less in synch with neurosteroid levels.

"If you want to maintain a constant level of inhibition, with more neurosteroids, you need fewer receptors," she explained. "After pregnancy, when hormone levels drop off, you need more receptors to maintain that level. If you cannot maintain that level after pregnancy, that's when the disorders manifest."

She and Mody reached that conclusion using mice genetically engineered to lack a particular component of the GABA receptor -- that is, mice that cannot adjust GABA receptor levels in response to changing hormone levels. By comparing these mutants to normal mice, the pair discovered that dysregulation of the normal changes in GABA receptor levels lead to mouse behaviors akin to postpartum depression, such as anxiety and depression, with a concomitant decrease in pup survival.

Treatment with THIP (Gaboxadol), a GABA receptor agonist originally intended to treat sleep disorders, ameliorated these effects in mice containing decreased levels of GABA receptors.

"Our thinking is that postpartum depression, and maybe premenstrual syndrome and premenstrual dysphoric disorder, may be due to impaired trafficking of these [GABA] receptors to the [neural] membrane," Mody said.

The next step, he said, is to determine whether human postpartum depression is caused by a similar defect.

"We don't know if this is the same mechanism in humans, but I think all indications are there," Mody said. "The women that are affected by the disorder, the hormone levels are not changed, they are not different than in unaffected women. So, we are confident that it must be the receptor trafficking mechanism that is affected, because the changes in hormone levels are pretty normal."

Dr. Julio Licinio, chairman of the department of psychiatry and behavioral sciences at the University of Miami Miller School of Medicine, praised the research as "very interesting," particularly its development of a new animal model of postpartum depression, which can aid both research and drug development.

"This is probably the strongest [animal] model I have seen in a long time," he said.

More information

For more on postpartum depression, visit womenshealth.gov.



SOURCES: Istvan Mody, Ph.D., Tony Coelho professor, neurology and physiology, department of neurology, David Geffen School of Medicine, UCLA; Jamie Maguire, Ph.D., assistant researcher, department of neurology, David Geffen School of Medicine, UCLA; Julio Licinio, M.D., professor and chairman, department of psychiatry and behavioral sciences, University of Miami Miller School of Medicine; Bernard Carroll, M.D., Ph.D., scientific director, Pacific Behavioral Research Foundation, Carmel, Calif.; July 31, 2008, Neuron


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