Postpartum depression affects nearly 20% of new mothers, with symptoms ranging from low mood, sadness, lack of energy, confidence, and appetite, and poor self esteem, to significant anxiety, guilt, suicidal thoughts, and difficulty bonding with the baby. Scientists at Tufts University School of Medicine have now developed a mouse model of postpartum depression that demonstrates direct involvement of the hypothalamic–pituitary–adrenal (HPA) axis, a neuroendocrine system that controls the body’s physiological response to stress—the fight or flight response—but which is normally switched off during and after pregnancy.

The researchers suggest that their results have highlighted a potential molecular target against which effective new treatments for postpartum depression can be developed. They also hope that the mouse model will provide new insights into the complex mechanisms that underlie postpartum depression, so that biomarkers can be found that identify vulnerable women. 

“Pregnancy obviously involves great changes to a woman's body,” comments Laverne Camille Melón, Ph.D., of the Tufts University School of Medicine department of neuroscience, first author on the authors’ published paper in Psychoneuroendocrinology (“Inability to Suppress the Stress-Induced Activation of the HPA Axis during the Peripartum Period Engenders Deficits in Postpartum Behaviors in Mice”). The authors point out that, “…we're only now beginning to understand the significant unseen adaptations occurring at the neurochemical and circuitry level that may be important to maintaining mental health and maternal behavior in the first few weeks to months following delivery.” 

The HPA axis is normally deactivated during and after pregnancy to help protect the developing baby from stress. Although it has been proposed that dysregulation of the HPA axis may play a key role in postpartum depression, studying this dysregulation directly hasn’t been possible because of a lack of useful animal models. And while animal experiments have shown that stress, or administering stress hormones, can induce abnormal postpartum behaviors, clinical data on stress hormones in women with postpartum depression have been inconsistent. Studies haven’t been able to demonstrate a role for corticotropin-releasing hormone (CRH)—the main driver of the stress response—or for inappropriate activation of the HPA axis in postpartum depression. CRH is primarily secreted by the paraventricular nucleus (PVN) in the hypothalamus.

“Some clinical studies show a relationship between CRH, HPA axis function, and postpartum depression, but others fail to replicate these findings,” comments corresponding author Jamie Maguire, Ph.D., assistant professor in the department of neuroscience at Tufts University School of Medicine. “Direct investigation into this relationship has been hindered due to the lack of useful animal models of such a complex disorder.”

Previous work by Dr. Maguire’s laboratory had shown that the brain protein KCC2 plays a role in regulating CRH neurons and the physiological response to stress. In their latest studies, the researchers first assessed KCC2 expression in the PVN of virgin, pregnant, and postpartum mice to investigate the specific role that KCC2 might play in regulating the HPA axis during and after pregnancy. They found that KCC2 was downregulated in virgin mice exposed to stress, but not in pregnant or postpartum mice.

The team then developed knockout mice that lacked KCC2 in CRH neurons and compared activation of the HPA axis in the knockout mice and in their wild-type littermates. The KCC2 knockout animals showed much more stress reactivity during the peripartum period than the control animals. Animals lacking CRH KCC2 also didn’t exhibit the reduced levels of anxiety that are typical of the postpartum period, but instead demonstrated abnormal maternal care compared with the normal animals. Applying techniques that activated or silenced CRH neurons allowed the researchers to pin the abnormal behaviors onto the activity of these neurons that govern the HPA axis.

“Here, we demonstrate that the normal suppression of the stress-induced activation of the HPA axis during the peripartum period involves maintenance of KCC2 in the PVN,” the authors write. “This study demonstrates that dysregulation of the HPA axis is sufficient to induce abnormal postpartum behaviors and deficits in maternal behaviors in mice, providing empirical support for a role of HPA axis dysfunction in the pathophysiology of postpartum depression.”

The results effectively show “for the first time that dysregulation of the HPA axis and a specific protein in the brain, KCC2, can be enough to induce postpartum depression-like behaviors and deficits in maternal care,” comments Dr. Maguire, who is also a member of the Neuroscience and Pharmacology & Experimental Therapeutics program faculties at Tufts' Sackler School of Graduate Biomedical Sciences.

The researchers suggest that the HPA axis will represent just one component in an interplay of mechanisms that underlie postpartum depression. “Many psychiatric and neurological disorders are a constellation of symptoms and represent an unfortunate synergy of heterogeneous maladaptations,” Dr. Melón continues. “The mechanisms underlying one woman's postpartum depression may differ from another's.”

The team hopes that their mouse model will help them to identify a biomarker that might indicate which pregnant women are more likely to develop postpartum depression, and potentially lead to new approaches to treating disorders characterized by KCC2 deficiency.  ‘“By uncovering the role for stability of KCC2 in the regulation of CRH neurons, the postpartum stress axis, and maternal behavior, we hope we have identified a potential molecular target for the development of a new class of compounds that are more effective for women suffering from postpartum depression and anxiety,” notes Dr. Melón.

“There is much more we need to learn,” Dr. Maguire notes, “but we believe our model will be useful for testing novel therapeutic compounds for postpartum depression. Such studies could also be relevant to other conditions in which KCC2 deficits are implicated, such as epilepsy, chronic pain, and autism, and to other stress- and anxiety-related disorders.”