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Even though nearly 15 per cent of women suffer from postpartum depression (PPD), we still don't know the definitive causes of PPD and why some women are affected by it while others aren’t. PPD can come on anytime in the first year postpartum and symptoms can include anxiety as well as depression including panic attacks, palpitations, intrusive thoughts and excessive worrying.

In an exciting recent study, researchers may be closer to determining one of the biological causes of PPD. A study published in the Journal of Psychoneuroendrocrinology discovered that lacking a specific protein results in deficits in postpartum behaviors. This protein is called KCC2 and is an important element in helping the body fight stress. It forms part of the hypothalamic-pituitary-adrenal axis or HPA axis for short which is normally suppressed during pregnancy. It’s thought that the dysregulation of the HPA axis could be one of the causes of PPD in women. Researchers haven’t been able to prove that however, due to the lack of adequate animal models.

In this latest study however, researchers from the Tufts University School of Medicine in Boston were able to use mice lacking the KCC2 protein and discovered that these mice displayed “dysregulation of the HPA axis and abnormal postpartum behaviors.”

Here is an interview with one of the researchers involved in this important study, Jamie Maguire, Assistant Professor at Tufts University School of Medicine’s Neuroscience Department, who agreed to answer questions for our readers to gain further insight into the implications of this study for women suffering from PPD:

Patricia: Why can’t we use women instead of mice to study the biological causes of PPD?

Jamie: Studies in patients with postpartum depression are incredibly useful and should not be discounted. In fact, it was studies from the clinic which informed our preclinical studies. However, many studies in patients are limited to correlative studies which are insufficient to determine causality. Identifying relevant changes in the patients with postpartum depression are also confounded by the fact that there are likely numerous underlying etiologies making it difficult to identify shared commonalities in a diverse patient population. Relevant to the current study, alterations in stress hormones have been identified in some clinical studies, but not in others again, likely due to the diversity in the patient population. The strength of using animal models is the ability to empirically test whether specific changes directly contribute to the outcomes being tested. In this case, we were able to build on correlative studies in humans suggesting that stress hormones may contribute to postpartum depression to directly demonstrate that dysregulation of the HPA axis, which controls the body’s physiological response to stress, contributes to postpartum depression-like behaviors in mice. These studies in mice demonstrate that HPA axis dysregulation is sufficient to induce abnormal postpartum behaviors, including depression-like behaviors and deficits in maternal care.

Patricia: How relatable are mice to women experiencing PPD?

Jamie: This is a very important question. Obviously, there are unique features of PPD which cannot be modeled in mice and we are careful to consider these differences when interpreting our findings in mouse models. However, many of the neuroendocrine changes which have been implicated in postpartum depression are shared between rodents and humans. Relevant to the current study, changes in ovarian hormones which are thought to precipitate the symptoms of PPD are similar in rodents (although on a shorter time scale since gestation in mice is only 21 days). Further, stress reactivity and HPA axis function are also similar between rodents and humans enabling us to directly investigate the impact of these neuroendocrine changes in PPD.

Patricia: What’s another way of saying "dysregulation of the HPA axis"?

Jamie: Our observations demonstrate that inappropriate stress reactivity during the peripartum period is sufficient to induce abnormal postpartum behaviors in mice, including depression-like behaviors and deficits in maternal care. This excessive stress signaling during the peripartum period is what we refer to as dysregulation of the HPA axis.

Patricia: Why has dysregulation of the HPA axis been proposed to play a role in postpartum depression?

Jamie: Evidence from patients with postpartum depression as well as experimental models have implicated HPA axis dysregulation in postpartum depression. Stress is known to be a significant risk factor for developing postpartum depression and clinical findings have suggested altered levels of stress hormones in patients suffering from postpartum depression. Experimentally, chronic stress or administration of exogenous stress hormones can induce depression-like behaviors and deficits in maternal care in postpartum mice. Here, we directly demonstrate that inappropriate engagement of the HPA axis during the peripartum period is sufficient to induce abnormal postpartum behaviors, including depression-like behaviors which are restricted to the postpartum period and deficits in maternal care.

Patricia: What can you tell us about KCC2?

Jamie: KCC2 is a protein. The protein functions as a transporter which transports chloride out of the cell and potassium into the cell. This transporter is responsible for maintaining low intracellular levels of chloride in the neurons in the adult nervous system – which is essential for GABAergic inhibition. GABA is the primary inhibitory neurotransmitter in the central nervous system and serves to constrain and coordinate the activity of principal neurons. The fast-synaptic effects of GABA are mediated by GABA receptors which flux chloride. Thus, the effectiveness of these receptors (and GABAergic inhibition) requires low intracellular levels of chloride which relies on KCC2 function. Thus, KCC2 plays a critical role in the effects of GABA in constraining and coordinating principal neuronal/network function.

Patricia: What role does KCC2 play in the regulation of the HPA axis during pregnancy and the postpartum period?

Jamie: We previously discovered that impaired KCC2 function, via dephosphorylation and downregulation of this protein, is required to overcome the GABAergic inhibition constraining HPA axis activity. Our evidence suggests that a decrease in KCC2 activity is required to mount the body’s physiological response to stress. During the peripartum period, stress reactivity is blunted. This recent study demonstrates that the suppression of stress reactivity during pregnancy and the postpartum period requires KCC2-mediated constraint of the HPA axis. Further, this study demonstrates that deficits in the KCC2-mediated regulation of the HPA axis is sufficient to induce peripartum HPA axis dysregulation and abnormal postpartum behaviors.

Patricia: What would cause a woman to lack KCC2?

Jamie: Mutations have been identified in KCC2; however, to my knowledge, no one has looked for mutations in KCC2 specifically in association with postpartum depression. Future studies are required to investigate the association of KCC2 mutations in patients with postpartum depression. In addition, alterations in KCC2 expression may result under other conditions which may impact the vulnerability to postpartum depression. For example, our previous studies demonstrated that chronic stress exposure can alter KCC2 expression in regions which control the HPA axis - potentially increasing vulnerability to postpartum depression based on our current findings.

Patricia: How will we able to determine/test whether a woman lacks KCC2 and if she did, when should she be tested and how should she be treated? Would this be the subject of future studies?

Jamie: We are currently investigating potential biomarkers for the identification of patients which may benefit from specific types of therapeutic intervention. For example, patients which exhibit HPA axis dysfunction may benefit from treatments which restore normal peripartum HPA axis function. In addition, we are conducting studies to identify markers which indicate responsiveness to specific treatments. These studies are ongoing. On a related note, the characterization of these preclinical PPD models is beneficial for attempts at identifying potential biomarkers as well as for screening potential novel treatments.

Patricia: Is this the first time the role of KCC2 in postpartum depression has been examined? What about the role of hormones and other biological and environmental factors that may cause PPD?

Jamie: Yes, this is the first time KCC2 has been investigated in postpartum depression. We identified a role for KCC2 in postpartum depression through a series of hypothesis-driven investigations into the role for HPA axis dysfunction in postpartum depression and the mechanisms of HPA axis regulation. However, there is still much we need to learn about how KCC2 is regulated during the peripartum period and how HPA axis dysfunction leads to PPD. For example, ongoing studies are investigating the role of ovarian hormones in the regulation of KCC2 and the activity of the HPA axis.

Patricia: What should scientists and researchers do with this information going forward?

Jamie: Recently, there has been a plea for increased mental health screening in postpartum women. It is important for clinicians to be aware of the risk for PPD. Further, given that stress is a significant risk factor for PPD, clinicians should be aware of this risk and inform their patients. Studies are ongoing using these preclinical models to investigate the underlying mechanisms contributing to PPD and assessing the effectiveness of novel treatments for PPD. These preclinical models are useful tools for investigation into PPD. Further, we hope that these findings spur interest in research on women’s health.

References:

Melon, L.C., Psychoneuroendocrinology (2017), https://doi.org/10.1016/j.psyneuen.2017.12.003

Patricia Tomasi, (2017), Huffington Post Canada, A Massive Postpartum Depression Study Just Opened In Canada, http://www.huffingtonpost.ca/2017/04/27/postpartum-depression-study_n_16272462.html

Andrea Lanes, Jennifer L Kuk, Hala Tamim, (2011), U.S. National Library of Medicine, Prevalence and characteristics of Postpartum Depression symptomatology among Canadian women: a cross-sectional study, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3118237/