The researchers decided to focus on the GABAA receptor for an important reason: the GABAA receptor is one of the principal targets for the action of many neuroactive products of steroid hormones that are usually called “neurosteroids.”
Altered neurosteroid levels have been associated with a wide variety of psychiatric illnesses, including premenstrual syndrome and postpartum depression. A large increase in levels of progesterone(Drug information on progesterone)-derived neurosteroids occurs during pregnancy, then levels decline rapidly after birth. Understanding how these levels interact with the GABAA receptor biology turned out to be an important area of inquiry.
The researchers noticed that GABAA receptor expression was greatly attenuated in the hippocampus of female mice during pregnancy. The loss of the receptor mediated a change in the electrical properties of the tissue, which was demonstrated by whole-cell, patch-clamp recordings (patch-clamp involves using electrodes to record currents in single neurons). Researchers also noticed that this effect was reversed in the postpartum period. The levels of the GABAA receptor rapidly returned to baseline after the females had given birth.
Knocking out the GABAA
How would an animal behave if it did not have this receptor or at least one of its subunits? If baseline levels could not ever return in these animals, would they exhibit depressive-like symptoms?
One way to answer this question would be to create knock-out mice that are raised without GABAA. Knock-out mice are genetically engineered to develop without a particular genetic sequence. They present the researcher with a site-specific loss of function. Hints as to the functioning of the knocked-out gene sequence can be obtained simply by noting abnormalities in the function or behavior of the animal (Figure).
It is a risky procedure. Some genes are so critical to gestational progress that their disruption results in the death of the animal, often in utero. The researchers knocked out only the g subunit we discussed previously. Without this subunit, receptor function is crippled. Happily, the animals survived.
The researchers were able to show depressive symptoms in the knock-out mice after birth. After the administration of the standardized Porsolt and anhedonia tests mentioned previously, the animals exhibited robust depressive characteristics. There was a disturbingly large increase in the overall pup mortality in this population. The manipulated mothers were much more likely to neglect or cannibalize their pups compared with unmanipulated littermate controls.
The last series of experiments involved the use of 4,5,6,7-tetrahydroisoxazolo(5, 4-c)pyridin-3-ol (mercifully shortened to THIP, also called “gaboxadol”). This drug, which was first characterized as a sedative, has an extraordinary property: it is a specific GABAA receptor g-subunit receptor agonist. THIP can fully restore GABAA receptor function, even in an animal that has lost its utility because of a subunit knock-out.
When these animals were treated with THIP, the depressive behaviors measured by the standardized tests and maternal behavior toward the pups vanished, and normal behavior was observed. The presence of functioning GABAA receptors appeared to be the independent variable in these experiments. Keep them present and normal behavior was observed. Reduce their levels (and inhibit their ability to reestablish themselves) and depression returns. You can turn it on and off like a light switch.
Could these data be used to explain postpartum depression? They certainly suggest compelling new lines of research. Remember that it is normal for elevated levels of progesterone-derived neurosteroids to down-regulate GABAA receptor concentrations during pregnancy and then to reestablish themselves after birth. Could postpartum depression in women be understood as an inability for these receptors to bounce back after birth? If so, it might be possible to test for such a lack of restoration with noninvasive imaging technologies. Is it possible that mutations in the receptor or in molecular moieties, which regulate receptor number, prevent their reestablishment to prepregnancy levels? Could these mutations predict depressive experiences? If so, the isolation of the first gene for postpartum depression might actually be in hand. Using THIP or its derivatives as a possible treatment, there may even be some hope for pharmacological intervention. Promising data indeed, but only promising.
My usual objections about applying animal research to human behavior hold here, certainly. The mouse cortex is, after all, about the size of a postage stamp, while the human cortex is about the size of a baby blanket. Compelling as these data are, they only suggest areas for human research directions.
These data do not solve the most common nature/nurture issues that dog most behavioral research like this, of course. It is especially important for affective disorders. Data suggest that the relative risk for depression is two-thirds environmental and one-third genetic. Because fathers can also experience depression, which can profoundly influence the spouse, that also must be factored in and perhaps saddled with more weight than other environmental influences.
None of these objections are deal killers. These data may point to the presence of a chromosomal abnormality as a risk factor for depression. It would then suggest that unusually close attention should be paid to any mother who has the chromosomal risk factor. These data may ultimately explain why the transition to parenthood (amateur sport that it is), although never easy for anyone, can be so catastrophically overwhelming to some.