Reporter: Howard Donohue, PhD (EAW)
The hypothalamic-pituitary-adrenal (HPA) axis – which can be thought of as a series of closely linked endocrine structures in the brain – has a key role in triggering the body’s stress response through the secretion of cortisol. In explaining how the HPA axis is itself regulated, for example how its activity is increased in response to a perceived environmental threat, we can infer that the diverse brain areas with which it shares neural interconnections have a crucial role (for a review, see ). An equally important question relates to how the activity of the HPA axis is returned to normal when the stress response is no longer needed. To answer this, it is well known that the same “neurosteroid” hormones released by the HPA axis that trigger stress-related biological adaptations also serve to dampen its activity through a “negative feedback” mechanism. In re-defining the biological model of how neurosteroids control the HPA axis, a study led by Jamie Maguire, PhD at Tufts University (Boston, MA) provides some fascinating insights . Moreover, this study has some extremely interesting and counter-intuitive implications for understanding the functions of the “inhibitory” brain chemical gamma-aminobutyric acid (GABA), which is best known for opposing the effects of “excitatory” brain chemicals in order to balance the flow of electrical activity in the brain.
To study how the HPA axis is regulated by neurosteroids, Maguire’s team performed investigations in mice using the neurosteroid tetrahydrodeoxycorticosterone (THDOC). The investigators found that THDOC, when applied to a discrete population of cells in the thalamus called the paraventricular nucleus (PVN), resulted in a decrease in blood levels of corticosterone (the mouse equivalent of the human stress hormone, cortisol). This finding highlights the importance of the PVN as a key anatomical locus in the brain where neurosteroids act, and is consistent with the traditional view of neurosteroids as “negative regulators” of the HPA axis. However, in mice that underwent a stressful “restraint” procedure, it was found that a prior treatment with THDOC (thirty minutes before the stressful experience) resulted in augmentation of corticosterone levels (i.e. relative to mice that underwent the stressful experience but did not receive prior THDOC treatment). In parallel, it was shown that while application of THDOC normally decreased the electrical activity of PVN cells, it actually led to increases in mice that had undergone restraint. Taken together, these findings provide evidence that neurosteroids can have opposite effects on the HPA axis depending on the “stressed” state of the organism.
Thinking about how a neurosteroid hormone can exert opposite effects on PVN cells in the thalamus may be confusing, but what may be more confusing is that these different actions depend on the same “inhibitory” brain chemical, GABA (a neurotransmitter), as well as the same molecular “machinery” (or receptors) with which GABA interacts. This was demonstrated by using mice in which a particular sub-component (or subunit) of the GABA receptor, the gamma subunit, had been genetically deleted; neurosteroids had absolutely no effect on the activity of the HPA axis (neither positive nor negative) in these gamma subunit-deficient mice.
How is it possible to explain the seemingly paradoxical finding that neurosteroids can exert opposite effects on the HPA axis through the same neurotransmitter system? In addressing this question, it is important to remember that although neurotransmitters may be thought of as excitatory or inhibitory, their ability to trigger these effects depends solely on the molecular and cellular apparatus with which they interact. Normally, the inhibitory actions of GABA upon the electrical activity of nerve cells depend on the maintenance of an “electrochemical” gradient by a “transporter” molecule called KCC2 (which transports chloride ions out of cells). Maguire’s team showed that “dephosphorylation” (i.e. the removal of a small chemical moiety – the phosphate group – which is covalently bound at a specific site on the molecule) of KCC2 resulted in lower detectable levels of this transporter in the PVN. Similarly to innumerable other examples in biology where dephosphorylation (or the reverse, phosphorylation) serves as an exquisite regulatory mechanism for controlling the activity of molecular networks, removal of the phosphate group from KCC2 acts as a molecular “switch” that causes the breakdown of the electrochemical gradient. The outcome is that GABA has an excitatory influence on neural activity instead of the inhibitory influence with which it is usually associated.
In common with many important contributions to scientific understanding, these findings should serve as a reminder that it is often necessary to challenge and question what is already “accepted” in our theoretical models, in the light of unexpected and sometimes counter-intuitive experimental results. Whatever the line of scientific inquiry may be, the reward for doing so will be a deeper and more comprehensive understanding of the natural phenomena being studied. The findings of Maguire and colleagues, published in the Journal of Neuroscience, have possible therapeutic implications for disorders associated with disrupted function of the HPA axis, including epilepsy and depression.