Wednesday, September 28, 2016

New Hope for New Moms

By Jacqueline Mitchell

Getting at the neurological roots of postpartum depression

Jamie Maguire

Jamie Maguire suspects using medications that target specific brain receptors “would address the pathology of the disease, rather than just boosting mood.” Photo: Kelvin Ma

It’s supposed to be a joyous occasion, but for some new mothers, as many as 20 percent across the globe, having a baby can bring on postpartum depression, a malady that arrives weeks or months after delivery and can linger much longer than the more common “baby blues.”

Like other forms of depression, it can entail persistent feelings of sadness and hopelessness, changes in sleeping and eating habits, extreme fatigue and loss of energy and even thoughts of suicide. It can interfere with the natural bonding between mother and baby, and may even impair the child’s development.

Now Jamie Maguire, an assistant professor at the School of Medicine, is working with a colleague at UCLA to identify the biological basis of postpartum depression. If successful, her research, whose initial findings appeared in the journal Nature in 2008, could lead to better screening, prevention and treatment for this life-altering condition.

Doctors long assumed postpartum depression was caused by a rapid drop in pregnancy hormones such as progesterone after delivery. But researchers a decade ago found this wasn’t true, and now the search is on for alternative hypotheses.

While working as an assistant researcher in the lab of Istvan Mody, the Tony Coelho Professor of Neurology at the UCLA School of Medicine, Maguire zoomed in on another chemical culprit: neurosteroids, compounds made in the body as the pregnancy hormones break down. Fluctuating neurosteroid levels have been implicated in a number of psychiatric disorders, including depression and anxiety, but the exact mechanisms underlying those illnesses remain unclear.

Neurosteroids seem to affect mood and behavior by bonding to the surface of brain cells at sites called GABA receptors. The number of GABA receptors on the surface of neurons is known to decline during pregnancy. Normally, neurons revert back to their pre-pregnancy state immediately after delivery. Maguire wondered if this process is disrupted in some women, leaving them vulnerable to postpartum depression.

Putting It to the Test

To test the role of GABA receptors in postpartum depression, Maguire and Mody compared the parenting skills of normal mice to those of mice with genetically altered GABA receptors. Sure enough, depression appeared more prevalent among the engineered mice—known as knockout mice, since the gene that would have led to standard-issue GABA receptors is deleted or switched off.

How can you tell a mouse is depressed? One method is the forced-swim test, in which researchers place mice in a pool of water with no way to get out. Typically mice will keep looking for a way out for most of the 10-minute trial.

Scientists assume the mice that give up sooner are depressed; their lack of effort seemingly results from something like the hopelessness and despair many people with depression experience. In addition, mice that respond poorly in the forced-swim test respond to antidepressant treatment, which has legitimized it as a measure for depression in rodents.

When Maguire and Mody performed the forced-swim test with their subjects, the postpartum knockout mice gave up about 20 seconds sooner than their normal counterparts.

More convincing is Maguire’s data regarding the survival rates of the pups. The GABA knockout mothers’ pups had much higher mortality rates. Additionally, these mothers were more likely to neglect their pups or engage in cannibalistic behavior.

To make sure the GABA knockout mothers weren’t responding to a genetic defect in their own babies, Maguire conducted another experiment, switching the litters so that the GABA knockout mothers were raising the normal mothers’ pups and vice versa. The behaviors persisted, and fewer normal pups raised by the GABA knockout mothers survived. Moreover, giving the knockout mothers a drug to counteract their genetic defect improved the survival of the pups under their care.

Now Maguire is studying other ways in which postpartum depression in the mother can affect offspring, with grant funding from the Charles Hood Foundation. She says she will use the same animal model to investigate whether “differences in offspring behavior and cognition happen via nurturing or by a biochemical process.”

And she’s already thinking about how her work might affect treatment options for postpartum depression. Today, many mothers with postpartum depression are prescribed SSRIs, the class of anti-depressants that includes Prozac, which are very effective in treating depression unrelated to the postpartum period. SSRIs work to increase the amount of serotonin—the neurotransmitter associated with a sense of well-being—available in the brain.

But Maguire suspects using medications that work on the GABA receptors, such as low doses of some sleep medicines already on the market, would “be a more targeted approach,” she says. “They would address the pathology of the disease, rather than just boosting mood.”

Jacqueline Mitchell can be reached at jacqueline.mitchell@tufts.edu.

Posted October 04, 2010