Gunn et al. GABAA receptors, neurosteroids, and stress and forebrain stress centers exhibit similar adaptations deserves is not simply correlated with substrate levels. These observa- further investigation as alterations in the neuronal architecture tions suggest that following stress exposure, the resultant elevated of these brain structures could signiﬁcantly amplify individual corticosterone levels may increase 3α-HSD expression and conse- stress vulnerability, or resilience. Moreover, epigenetic adaptations quently, increase the levels of neurosteroids probably via classical resulting from speciﬁc mother–pup interactions have the poten- genomic mechanisms. However, glucocorticoids can additionally tial to be transmitted across subsequent generations to impact on exert rapid, non-genomic effects in a number of stress-related their susceptibility to stress exposure (Weaver et al., 2004; Tsankova brain structures (Tasker and Herman, 2011), and such actions may et al., 2007; Murgatroyd et al., 2009; Brunton and Russell, 2011; contribute to curtailing HPA activity (Tasker and Herman, 2011). Curley et al., 2011). The molecular mechanism of rapid glucocorticoid signaling, and In agreement with animal models of postnatal stress, studies the impact of this steroid hormone upon neuronal excitability in human subjects have revealed that early stress has a signiﬁ- appears to be brain region, neuron, and even synapse speciﬁc (Di cant negative impact upon brain development and function in et al., 2003, 2005, 2009; Karst et al., 2005, 2010; Tasker and Herman, children, which may predispose individuals to develop affective 2011). For example, in magnocellular neurons of the supraoptic disorders in adulthood (reviewed in Repetti et al., 2002; McEwen, nucleus (SON) and PVN, glucocorticoids activated divergent G- 2003). Speciﬁcally, the timing and severity of early life stress has protein signaling pathways to inhibit and increase the release of been postulated to induce pathophysiological alterations within glutamate and GABA respectively, in a synapse-speciﬁc manner the CNS that increases the stress vulnerability of individuals, pre- (Di et al., 2009). Glucocorticoid-induced endocannabinoid syn- disposing them to psychiatric disorders in later life (McGowan thesis and retrograde signaling speciﬁcally inhibited glutamate et al., 2009; Neigh et al., 2009). Consistent with this proposal, epi- release, while an enhanced GABA release has been associated genetic reductions in hippocampal glucocorticoid feedback have with the rapid stimulation of nitric oxide (NO) synthesis (Di been associated with childhood abuse and increased risk of suicide et al., 2009). Rapid glucocorticoid effects are dependent upon (McGowan et al., 2009), an effect that is analogous to alterations G-protein and protein kinase activation as endocannabinoid syn- in hippocampal GR expression in rats exposed to low quality of thesis results from Gαs-induced production of cAMP and the maternal care (Weaver et al., 2004). subsequent activation of PKA, whereas the activated Gβγ dimer Whether in humans early life stress induces alterations of neu- leads to activation of nNOS and NO synthesis. Whether such sig- rosteroid levels, similar to those described for a variety of animal naling pathways can stimulate neurosteroidogenesis is currently models is currently not known, but if so they may be of patho- unknown, although the recent report that NMDA receptor acti- logical relevance. Indeed, normalization of such levels may be vation stimulated neurosteroidogenesis via similar downstream therapeutically beneﬁcial in a manner similar to that reported signaling pathways (i.e., MAPK, nNOS; Tokuda et al., 2011) sug- for depressed patients (Uzunov et al., 1996). In this respect, the gests the possibility of an analogous scenario (Figure 1). Further- recent demonstration that XBD173 stimulates the synthesis of more, it is plausible that the impact of an NO-induced increase in GABAAR-active steroids and in humans this drug acts as an effec- GABA release upon the inhibitory tone exerted on hypothalamic tive anxiolytic, suggests that novel therapeutic strategies for the magnocellular neurons could be further ampliﬁed by neurosteroid treatment of early stress-related disturbances may be possible potentiation of GABAAR function. Indeed, neurosteroids, such as (Rupprecht et al., 2009). 5α3α-THPROG, acting at presynaptic GABAARs, typically cause an increase in synaptic transmission (Haage et al., 2002; Uchida REGULATION OF NEUROSTEROID SYNTHESIZING ENZYMES; et al., 2002; Ruiz et al., 2010) due to the excitatory actions of A ROLE FOR GLUCOCORTICOIDS AND NEUROPEPTIDES? GABA on presynaptic terminals (Kullmann et al., 2005; Szabadics Although acute stress rapidly elevates brain neurosteroid levels in et al., 2006; Trigo et al., 2008). Thus, following a stressful challenge, rodents (Purdy et al., 1991), the mechanism(s) by which a stressor locally produced neurosteroids may potentially modulate synaptic induces neurosteroidogenesis is currently unknown. Indeed, rel- transmission via actions at both pre- and postsynaptic GABAARs atively little is known regarding the mechanisms responsible for (Figure 2C). regulating the activity of steroid synthesizing enzymes and trans- Intriguingly, in rodents both CRH and ACTH elevate the porters such as TSPO, 5α-reductase, and 3α-HSD within the CNS. brain and plasma levels of 5α3α-THPROG (Torres et al., 2001). However, a recent study indicates that NMDA receptor activation Similarly, in humans plasma levels of this neurosteroid were can rapidly (within 5 min) increase the levels of neurosteroids elevated following CRH administration (Bernardi et al., 2000). in hippocampal CA1 neurons (Tokuda et al., 2011), possibly sig- These observations are consistent with the proposal that neu- naling via p38 mitogen-activated protein kinase (MAPK), neu- rosteroids may be implicated in curtailing HPA axis activity. ronal nitric oxide synthase (nNOS), and calcineurin (Izumi et al., Although it is unclear whether CRH directly stimulates neu- 2008; Figure 1). Additionally, certain steroid hormones, e.g., cor- rosteroid synthesis (see below on Neurosteroids and Ethanol), ticosterone and estrogen, as well as the neuropeptide CRH, can a growing body of evidence indicates that CRH and its related modulate the levels of endogenous neurosteroids in a gender and peptides (i.e., the urocortins) have extra-hypothalamic molecular steroid-speciﬁc manner (Torres et al., 2001; Mitev et al., 2003). targets and, for example, may modulate synaptic transmission in For example, Mitev et al. (2003) have reported corticosterone to stress–sensitive regions such as the CeA, mPFC, and BST (Swan- increase 3α-HSD expression in both genders. In contrast, proges- son et al., 1983; Bale and Vale, 2004; Gallagher et al., 2008). terone, a precursor of 5α3α-THPROG had no effect upon 3α-HSD Thus, it is conceivable that CRH-induced neurosteroidogenesis expression in either gender, indicating that the activity of 3α-HSD may inﬂuence neurotransmission in a number of limbic and www.frontiersin.org December 2011 | Volume 5 | Article 131 | 11