Gunn et al. GABAA receptors, neurosteroids, and stress FIGURE 2 | A model for neurosteroid actions at the GABAA receptor within the stress neurocircuitry. (A) A diagrammatic representation of the HPA axis. The release of CRH from the dorsal–medial parvocellular neurons (mpd) of the PVN is regulated by humoral negative feedback pathways and neuronal inputs from higher brain structures (e.g., the limbic system and the forebrain regions). Inputs from the forebrain and the limbic structures do not directly innervate the PVN, but form polysynaptic connections via a number of predominantly GABAergic “relay nuclei” (red) surrounding the PVN, such as the BST mPOA, DH, and peri-PVN (Cullinan et al., 2008). In the proposed model stress-induced endogenous neurosteroids derived from peripheral sources (e.g., 5α3α-THDOC) and or synthesized de novo within the CNS (e.g., 5α3α-THPROG) may act to enhance the GABAergic inhibition in the PVN and surrounding neurons. Additionally, neurosteroids may modulate inhibitory transmission within limbic and forebrain regions to inﬂuence their neuronal output and hence HPA activity. (B) Physiological concentrations of 5α3α-THPROG (100 nM) dramatically reduce the frequency of action currents recorded from WT mpd neurons in a hypothalamic slice preparation containing the PVN and surrounding structures, thus inhibiting their output (i.e., CRH release). Local excitatory inputs (e.g., glutamatergic, green), which are themselves constrained by inhibitory GABAegic neuron (red) originating in the BST and local hypothalamic nuclei (Herman et al., 2002) drive the release of neuropeptides from mpd neuron (gray) of the PVN. (C) A diagrammatic representation of a representative PVN synapse (either GABAergic or glutamatergic). Neurosteroids (e.g., 5α3α-THPROG) synthesized following a stressful challenge, may act both at presynaptic or postsynaptic locations in an autocrine or paracrine fashion respectively to enhance GABAAR inhibition. Note that at presynaptic terminals due to the intraneuronal Cl− gradient, GABA may be depolarizing (Trigo et al., 2008) and thus neurosteroids may act to increase neurotransmitter release. Note that although extrasynaptic δ-GABAA receptors are absent in the PVN, other γ2-GABAARs may be expressed extrasynaptically at GABAergic or glutamatergic synapses. whilst the membrane-bound isoform promotes the reverse, oxida- tive reaction (Li et al., 1997). In DGGCs the membrane-bound 3α-HSD isoform is predominant, and the inhibition of this enzyme with indometacin, or the contraceptive agent Provera (Figure 1), results in a modest prolongation of miniature IPSCs (mIPSCs) and an enhancement of the endogenous tonic conductance of DGGCs (Belelli and Herd, 2003). Collectively, these observations are con- sistent with the proposal that local metabolism may play a crucial role in shaping GABAAR-mediated inhibition in a neuron-speciﬁc fashion. The translocator protein 18 kDa [TSPO; formerly the mitochondrial benzodiazepine receptor (MBR) or peripheral benzodiazepine receptor (PBR); Figure 1; Papadopoulos et al., 2006; Batarseh and Papadopoulos, 2010], is located on the outer mitochondrial membrane where it functions together with the steroidogenic acute regulator protein (StAR; Sierra, 2004; Figure 1) to transport cholesterol into mitochondria, a prereq- uisite and the rate-limiting step for steroid and neurosteroid synthesis (Rupprecht et al., 2010). The anxiolytic drug etifox- ine, in addition to allosterically enhancing GABAAR function, Frontiers in Neuroscience | Neuroendocrine Science December 2011 | Volume 5 | Article 131 | 4