GABA neurotransmitters have long been implicated in various psychiatric
disorders, say, generalized anxiety disorder, panic disorder, and
posttraumatic stress disorder. Now, research suggests that a subunit of a
receptor for GABA called the delta subunit of the GABAA receptor
seems to play a critical role in postpartum depression—at least in an
animal model.
The research was conducted by Jamie Maguire, Ph.D., and Istvan Mody, Ph.D.,
neurology-physiology scientists at the University of California, Los Angeles.
Results were published in the July 31 Neuron.
Researchers had suspected that postpartum depression might stem from a
rapid and dramatic decline in the reproductive hormone progesterone following
pregnancy. Yet experimental manipulation of progesterone in women with and
without a history of postpartum depression seemed to rule this out. So it
looked as if something other than progesterone was the culprit in postpartum
depression.
Enter Maguire and Mody. They took brain tissue from nonpregnant mice,
pregnant mice, and postpartum mice and examined the activity, in the brain
tissue samples, of the delta subunit of the GABAA reception. They
found that the subunit's activity differed depending on the sample from
which it came. It was less active in pregnancy than in nonpregnancy, yet it
was just as active postpartum as in nonpregnancy. In other words, it looked as
if the subunit became less active during pregnancy, then rebounded to a normal
state after birth. So Maguire and Mody suspected that the subunit might play a
pivotal role in postpartum depression and tested that hypothesis.
Twenty-three female mice were genetically engineered so that they did not
contain the subunit. They were then bred and, after giving birth, were
observed. Finally, their behaviors were compared with those of nine postpartum
female mice possessing the subunit (controls). The mouse mothers lacking the
subunit not only engaged in depression-like behaviors, but also in abnormal
postpartum behaviors, such as not building proper nests and neglecting their
pups. And significantly fewer of their 136 pups survived than did the 53 pups
of the control mouse mothers. So it looked as if the subunit might truly be
complicit in postpartum depression, at least in a mouse model of postpartum
depression.
And the case grew even stronger when the researchers gave five female mice
lacking the subunit a drug known to restore its function. The drug, called
THIP, is a selective GABAAR agonist. When these mice became
mothers, they acted maternally, and their 32 pups experienced significantly
greater survival than did the 90 pups of 15 new mouse mothers lacking the
protein and not getting THIP.
In an accompanying editorial, Charles Nemeroff, M.D., chair of psychiatry
at Emory University, wrote, "Depression during pregnancy and in the
postpartum period is common, devastating to mothers and their offspring, and
poorly understood in terms of pathophysiology.... [The findings by Maguire and
Mody] likely represent an incremental breakthrough in the field."
In a prepared press statement, Thomas Insel, M.D., director of the National
Institute of Mental Health, said that the research "points to a specific
potential new target in the brain for medications to treat [postpartum
depression] ... [and] for the first time, we may have a highly useful model of
postpartum depression."
As Maguire and Mody wrote in their study report, "Our data are
consistent with the idea that the pathophysiology of postpartum depression may
be related to the inability to properly regulate GABA ... during pregnancy and
postpartum."
The research was funded by the National Institute of Mental Health,
American Epilepsy Foundation, and UCLA Center for the Neurobiology of
Stress.
An abstract of "GABAAR Plasticity During
Pregnancy: Relevance to Postpartum Depression" is posted at<www.neuron.org/content/article/abstract?uid=PIIS0896627308005370>.▪