Researchers have pinpointed a mechanism in the brains of mice that could explain why some human mothers become depressed following childbirth. The discovery could lead to improved treatment for postpartum depression. Supported in part by the National Institute of Mental Health, of the National Institutes of Health, the study used genetically engineered mice lacking a protein critical for adapting to the sex hormone fluctuations of pregnancy and the postpartum period.
"For the first time, we may have a highly useful model of postpartum depression," said NIMH Director Thomas R. Insel, M.D. "The new research also points to a specific potential new target in the brain for medications to treat this disorder that affects 15 percent of women after they give birth."
"After giving birth, female mice deficient in the suspect protein showed depression-like behaviors and neglected their newborn pups," explained Istvan Mody, Ph.D., of the University of California at Los Angeles, who led the research. "Giving a drug that restored the protein's function improved maternal behavior and reduced pup mortality."
Mody and Jamie Maguire, Ph.D., report on their findings in the July 31, 2008 issue of Neuron.
Researchers had suspected that postpartum depression stemmed from the marked fluctuations in estrogen and progesterone that accompany pregnancy and childbirth. Yet manipulating the hormones experimentally triggers depression only in women with a history of the disorder. The roots of their vulnerability remain a mystery.
Evidence suggested that the hormones exert their effects on mood through the brain's major inhibitory chemical messenger system, called GABA, which dampens neural activity, helping to regulate when a neuron fires.
Mody and Maguire discovered that a GABA receptor subunit fluctuated conspicuously during pregnancy and postpartum in the brains of female mice, hinting that it might have pivotal behavioral effects. To find out, they used mice lacking the gene for this subunit and studied them in situations that can elicit responses similar to human depression and anxiety.
Much like human mothers suffering from postpartum depression, the genetically altered mouse mothers were more lethargic and less pleasure-seeking than normal mice. They also shunned their pups and failed to make proper nests for them.
This abnormal maternal behavior was reversed and pup survival increased after the researchers gave the animals a drug called THIP that acts on the receptor in a way that specifically restores its function in spite of the reduced number of subunits.
"Improper functioning of the subunit could impair the GABA system's ability to adapt to hormone fluctuations during the highly vulnerable post partum period," explained Maguire. "Targeting this subunit might be a promising strategy in developing new treatments for postpartum depression."
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