Science Editor

Estimates vary, but postpartum depression affects anywhere from 5 percent to 25 percent of women who give birth, making for at least 200,000 cases annually in the U.S. But little is known about why some women succumb to this form of depression, which can occur up to a year after giving birth.

The favorite, and often glib, explanation for what ails women tends to be "hormones," and the neurosteroid hormones are certainly on a roller coaster during and after pregnancy. But, Jamie Maguire told BioWorld Today, "steroid hormone levels are usually normal in women with postpartum depression."

Maguire is a postdoctoral researcher at the University of California, Los Angeles, and the first author of a paper in the July 31, 2008, issue of Neuron that sheds some light on the neural underpinnings of postpartum depression. Maguire and senior author Istvan Mody showed that mice whose GABA receptors lack one kind of subunit, the delta subunit, showed symptoms that are reminiscent of postpartum depression, and that specifically stimulating the delta subunit could compensate for its low levels in partial knockouts.

The neurotransmitter GABA is the major inhibitory transmitter in the brain. Its receptors, Maguire said, are made up of varying mixes of five different subunits and can play many different roles depending on their exact composition. Receptors with delta subunits appeared to provide a constant, baseline level of inhibition in the brain. Maguire and Mody decided to investigate their possible role in postpartum depression because neurosteroids bind to delta subunit-containing receptors.

During pregnancy, Maguire explained, neurosteroid levels rise vastly, and the brain reacts by down-regulating its levels of a delta subunit-containing GABA receptors "as a homeostatic mechanism to prevent sedation during pregnancy." After pregnancy, those hormone levels drop suddenly and sharply; women need to respond by once again increasing their levels of delta-containing GABA receptors. The work in Neuron suggested that postpartum depression may result from a failure to increase delta-containing GABA receptors.

Maguire and Mody first investigated the levels of delta subunit-containing GABA receptors in pregnant mice and found that mice did indeed have lower levels of that receptor subtype during pregnancy, and that levels increased once more after giving birth. They then studied mice lacking either one or both copies of the GABA receptor's delta subunit gene. They found that both groups of mice showed behavioral abnormalities specifically after giving birth that resembled those seen in human mothers with postpartum depression: They neglected their pups, failed to make proper nests for them, and in general, were less pleasure-seeking, and simultaneously more lethargic and more anxious, than controls.

Moreover, the scientists were able to reverse those symptoms in mice with low levels of delta subunits by adding a drug to their drinking water that specifically binds to delta subunit-containing GABA receptors: THIP, or Gaboxadol.

THIP was developed by Merck & Co. Inc., of Whitehouse Station, N.J., and H. Lundbeck A/S, of Copenhagen, Denmark, for the treatment of insomnia. But the companies pulled the plug on it in 2007, citing both lack of efficacy and safety concerns.

The new data, Maguire said, suggested that "at lower, nonefficacious doses for sleep, it might actually be effective against the symptoms of postpartum depression."

Whether or not Gaboxadol gets a second lease on life as a postpartum depression drug, the existence of an animal model that specifically mimics postpartum depression will allow scientists to test other therapeutic approaches to postpartum depression, as well as probe its basic mysteries. Maguire said she and her colleagues plan to screen women with postpartum depression, as well as premenstrual syndrome, to check for abnormalities in their levels of delta subunit-containing GABA receptors, and the researchers hope that their knockouts "will foster further insights into the mechanisms of postpartum depression and will provide much needed therapeutic potential for the large number of women suffering from mood disorders during early motherhood."