GABAergic control of the hypothalamic- pituitary-adrenal (HPA) axis: Role of extrasynaptic GABAA receptors

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.