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GABAergic Control of the Hypothalamic–Pituitary–Adrenal (HPA) Axis: Role of Extrasynaptic GABAA Receptors

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Book cover Extrasynaptic GABAA Receptors

Part of the book series: The Receptors ((REC,volume 27))

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Abstract

The body’s physiological response to stress is mediated by the hypothalamic–pituitary–adrenal (HPA) axis, the activity of which is tightly regulated by GABAergic inhibition. Parvocellular neurosecretory neurons located in the paraventricular nucleus (PVN) of the hypothalamus which release corticotropin-releasing hormone (CRH) govern the output of the HPA axis. CRH neurons are innervated by a high density of GABAergic terminals and are regulated by robust GABAergic inhibition. Furthermore, numerous other brain regions, including the hippocampus, prefrontal cortex, bed nucleus of the stria terminalis (BNST), and amygdala, exert control over the HPA axis via indirect GABAergic connections onto CRH neurons. CRH neurons express numerous γ-aminobutyric-acid type-A receptor (GABAAR) subunits and are regulated by both phasic and tonic GABAergic inhibition, mediated by synaptic and extrasynaptic GABAARs, respectively. The GABAergic control of the HPA axis is highly plastic and is altered by both acute and chronic stress. Here, I review the role of extrasynaptic GABAARs in the regulation of the HPA axis and the physiological response to stress.

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Authors and Affiliations

  1. Department of Neuroscience, Tufts University School of Medicine, 136 Harrison Ave., SC205, 02111, Boston, MA, USA

    Jamie Maguire

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  1. Jamie Maguire
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Correspondence to Jamie Maguire .

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Editors and Affiliations

  1. Neuroscience and Mental Health Research Institute, Institute of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Cardiff, United Kingdom

    Adam C. Errington

  2. Dept. of Physiology & Biochemistry, University of Malta, Msida MSD, Malta

    Giuseppe Di Giovanni

  3. School of Biosciences, Cardiff University, Cardiff, United Kingdom

    Vincenzo Crunelli

Concluding Remarks

Concluding Remarks

This review clearly demonstrates a role for extrasynaptic GABAARs in the regulation of the HPA axis at the level of CRH neurons as well as in other brain regions controlling HPA axis function, including the hippocampus, prefrontal cortex, BNST, and amygdala. Given the widespread anatomical distribution of extrasynaptic GABAARs and the differing impact of these numerous brain regions on the regulation of the HPA axis , it is difficult to interpret the net effect of these receptors on HPA axis function. Furthermore, the neurosteroid sensitivity of extrasynaptic GABAARs provides another level of complexity for the role of these receptors in the regulation of the stress response. Despite the complex role of extrasynaptic GABAARs in the regulation of the HPA axis, it is evident that these receptors influence HPA axis function. Our limited knowledge of the role of extrasynaptic GABAARs is largely due to the sparse number of studies investigating the synaptic regulation of the HPA axis, which is gaining considerable interest in the scientific community (Levy and Tasker 2012; Wamsteeker and Bains 2010) , let alone the limited number of studies directly investigating the role of extrasynaptic receptors in the regulation of the HPA axis. Additional studies are required to fully appreciate the contribution of extrasynaptic GABAARs on the regulation of the HPA axis.

Stress is known to either worsen or trigger illnesses ranging from the common cold to cancer (for review, see Cohen 2007) . Furthermore, hyperexcitability of the HPA axis has been implicated in the pathophysiology of numerous disorders, including depression (for review, see Lloyd and Nemeroff 2011; Pariante and Lightman 2008) . Therefore, insights into the regulation of the HPA axis may identify novel targets for therapeutic intervention, such as extrasynaptic GABAARs. Very few studies have investigated which GABAAR subtypes play a role in the regulation of the HPA axis. However, this book chapter has highlighted the importance of GABAergic inhibition on HPA axis function. Additional studies are required to fully appreciate the mechanisms regulating HPA axis function. However, we are optimistic that HPA axis modulation may be a feasible therapeutic target. Given the evidence that there may be independent mechanisms regulating basal glucocorticoid secretion and stress-induced glucocorticoid (Kammerer et al. 2006; Sarkar et al. 2011) , we support revisiting HPA axis modulation as a therapeutic target.

Acknowledgments

J.M. is funded by NS073574.

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Maguire, J. (2014). GABAergic Control of the Hypothalamic–Pituitary–Adrenal (HPA) Axis: Role of Extrasynaptic GABAA Receptors. In: Errington, A., Di Giovanni, G., Crunelli, V. (eds) Extrasynaptic GABAA Receptors. The Receptors, vol 27. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1426-5_12

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