Is There a Gene for Postpartum Depression?
Is There a Gene for Postpartum Depression?
The transition to parenthood is filled to the brim with behavioral extremes. Parents who are otherwise emotionally stable are in one moment thrilled and happier than they have ever been and confused and fearful the next. Afriend of mine once theorized that these reactions occur because "parenting is an amateur sport" played by persons who are highly motivated to do the right thing but who often have no idea what that right thing is.
For some couples, the transition to parenthood is not filled with this rich mixture of great perplexity and great joy. For them, parenthood is mostly filled with sadness and even despair. Postpartum depression was originally coined to describe this experience in the mother, although it is becoming clear that fathers can experience very similar emotions too.
Is there a molecular basis for postpartum depression—at least for the type that mothers experience? Recent findings, which I describe here, may answer this question. First, we will focus on several background behavioral and molecular issues and then move on to some interesting data about births in genetically manipulated laboratory animals. Feel free to skip to the “Data” section if postpartum depression rates and g-aminobutyric acid (GABA) receptor biology are working parts of your vocabulary.
As you know, the probability of experiencing major depression is twice as high in women as it is in men, and pregnancy does not buffer against this risk. Postpartum depression afflicts about 20% of mothers. Higher rates are seen in adolescent mothers than in older mothers.
Mental health professionals who are considering treatment for a depressed pregnant patient must make choices that can be particularly troublesome. Many clinicians are concerned about the potentially damaging effects of antidepressant medications on the developing fetus. Should a woman be treated during pregnancy? As I have discussed in this space before, serotonin plays a dramatic role in gestational brain development, especially in the thalamus. Concerns about serotonin’s effects on brain development actually held up the FDA’s approval of fluoxetine.
This risk is also observable after parturition. If depression remains untreated, the risk of drug and alcohol abuse and suicide and infanticide greatly increases. Yet, psychotropic drugs may expose a breast-fed baby to these medications. Are there risks associated with this exposure? The possibility of adverse consequences is not zero, although there is a critical need for further research in this area. As if pregnancy were not complicated enough, balancing the risk of potential behavioral consequences of depression with the pharmacological risk of treatment is quite challenging indeed.
There is increasing evidence that men can also experience depression after the birth of their child. The rates can be astonishingly high—about 1 in 4 fathers are affected in some studies; this rate climbs to 1 in 2 if his spouse is also depressed. The effect can be recursive. Loss of emotional support from the female because of depression may cause or exacerbate depression in the male, which in turn may retrigger depressive behaviors in the female.
Depression is a big deal for some families in the transition to parenthood; it is thus gratifying to report some very promising findings regarding its molecular underpinnings. We need only one more piece of background information, which involves a very particular animal model of depression, to understand it fully.
Molecular background issues
The literature that reviews the molecular processes in human depression often focuses on the seminal roles of catecholamines and indoleamines. Over the years, it has become increasingly clear that other neurotransmitter systems can also mediate the pathogenesis of depression, notably glutamate and GABA. One of GABA’s attendant receptors plays a prominent role in our story.
Often contrasted with glutamate (the canonical excitatory neurotransmitter), GABA is characterized as the brain’s classic “inhibitory” neurotransmitter. Glutamate and GABA function together as a kind of molecular yin-yang by regulating neuronal activity throughout the CNS. GABA mediates its effects by binding to 1 of 3 transmembrane receptors in specific neurons in the brain (awkwardly called “GABAergic” cells). The binding results in the opening of ion channels, creating a localized increase in the negativity across the plasma membrane. This hyperpolarization of the cell (as opposed to depolarization, which results in a more equal distribution of charge across the membrane) produces the inhibitory effect.
GABA is not always inhibitory. Most of its electrical effects depend on localized current flow in adult cells and even the stage of the development of the cell. In neonatal tissues, GABA acts as an excitatory neurotransmitter and makes a change in its job description only as the tissues mature.
As noted, GABA exerts its effects by binding to 1 of 3 members of the GABA receptor family: GABAA, GABAB, and GABAC. GABAA and GABAC are ionotropic receptors. As their name implies, these receptors function directly as the ion channels. GABAB opens ion channels in a less direct fashion. A classic metabotropic receptor, GABAB is g protein-coupled and participates in a signal transduction process that eventually results in the opening of other ion channels. These proteins are complex structures that are composed of smaller subunit proteins (the GABAA receptor has one called the “g subunit,” which will be important to our story).
Before we get started on the data, it might be useful to go over one last critical issue. Over the years, a number of animal models have been used to increase our understanding of the molecular substrates undergirding developmental processes. Although there have been a fair number of animal models that mimic aspects of human anxiety disorders, relatively few can be reliably used in the study of human depression.
One of the animal tests that is used often involves creating standardized depressive behavior in mice using the Porsolt forced swim test. Another test involves measuring anhedonia, in which the ability to experience pleasure from normally pleasurable activities is inhibited. Both were deployed in the data that I will describe next.