Gunn et al. GABAA receptors, neurosteroids, and stress (PTSD), and Alzheimer’s (Holsboer, 2000; Schule et al., 2009). Furthermore, the levels of endogenous neurosteroids in plasma and cerebrospinal ﬂuid (CSF) are altered in patients suffering from various stress-related affective disorders (Uzunova et al., 2006). Neurosteroids, chronic stress, and brain plasticity Chronic stress exposure results in a number of functional and molecular adaptations including altered dendritic morphology in stress-related brain regions such as the mPFC (Radley et al., 2005, 2008; Liston et al., 2006; Goldwater et al., 2009), hip- pocampus (Woolley et al., 1990; Magarinos and McEwen, 1995), and amygdala (Mitra and Sapolsky, 2008). These alterations in dendritic morphology are accompanied by behavioral changes, including impaired cognitive function (Bodnoff et al., 1995), increased anxiety (Mitra and Sapolsky, 2008), and abnormal atten- tional set-shifting (Liston et al., 2006). Interestingly, the observed stress-induced dendritic remodeling appears to be reversible, pro- vided animals receive appropriate recovery time following stress exposure (Radley et al., 2005; Goldwater et al., 2009). Chronic stress-induced morphological alterations appear to be mediated by both sex and stress hormones (e.g., estrogen, glucocorticoids) and are accompanied by changes in synapse formation and receptor expression (Joels et al., 2007; McEwen, 2010). Thus, the behav- ioral deﬁcits associated with chronic stress may be a consequence of network disruption in corticolimbic areas, an effect that may be contributed by, and secondary to, the remodeling of dendritic architecture within these brain structures (Goldwater et al., 2009). Relatively little is known regarding the inﬂuence that endoge- nous neurosteroids have upon the morphological alterations asso- ciated with chronic stress and major depression. However, the regenerative potential of 5α3α-THPROG has been explored in animal models of Alzheimer’s disease, the pathogenesis of which has recently implicated chronic stress as a signiﬁcant contribut- ing factor (Sotiropoulos et al., 2011). The proliferative effects of neurosteroids have been demonstrated in vitro using cerebellar granule cells (Keller et al., 2004), rat hippocampal, and human cortical neural progenitor cells (Wang et al., 2005), raising the possibility that the regenerative potential of neurosteroids may be therapeutically beneﬁcial (Wang et al., 2008). In a mouse model of Alzheimer’s disease (3xTgAD), male adult (3 months old) 3xTgAD mice displayed signiﬁcant reductions in cell proliferation in the hippocampal subgranular zone (SGZ) and behaviorally exhibited deﬁcits in a hippocampal associative learning and memory task, i.e., trace eye blinking conditioning (Wang et al., 2010). Intrigu- ingly, in the 3xTgAD mouse, 5α3α-THPROG, in a dose-dependent manner, signiﬁcantly increased cell proliferation in the SGZ to levels found in corresponding wild type mice, whilst also revers- ing the cognitive deﬁcits (Wang et al., 2010). Indeed, the survival of early progenitor cells in the 3xTgAD mouse correlated with the enhanced memory performance produced by 5α3α-THPROG treatment, suggesting that early neurogenic deﬁcits may contribute to the cognitive phenotype associated with Alzheimer’s disease. Therefore, such neurosteroids may potentially serve as a regenera- tive therapeutic, to alter the development and progression of such neurodegenerative diseases (Wang et al., 2010). Indeed, a recent study has revealed that 5α3α-THPROG restored neural progen- itor cell survival and associative learning and memory in adult male 3xTgAD mice that only exhibit intraneuronal amyloid β (Aβ; i.e., ≤9 months old). By contrast, the neurosteroid was ineffec- tive in later stages of the disease (at the age of 12 months) when extraneuronal Aβ plaques become apparent (Singh et al., 2011). Collectively, these ﬁndings indicate that the therapeutic efﬁcacy of this neurosteroid is dependent upon the stage of AD pathology. Intriguingly, there appears to be many similarities between the endocrine (e.g., hypersecretion of glucocorticoids) and neuronal (e.g., dendritic remodeling) modiﬁcations reported in the patho- genesis of both Alzheimer’s and depression (Lupien et al., 2009). Thus, it is tempting to speculate that the regenerative potential of 5α3α-THPROG observed by Wang et al. (2010) in a mouse model of Alzheimer’s disease may also reduce the depressive-like behav- iors and cognitive deﬁcits associated with prolonged chronic stress exposure. The ability of neurosteroids to increase cell proliferation and to restore corticolimbic network function may contribute to the putative antidepressant actions of certain steroids (Uzunova et al., 1998). Of interest, in patients suffering from Alzheimer’s disease the levels of the endogenous neurosteroid 5α3α-THPROG are reduced throughout the brain, but particularly in stress-related brain structures such as the hippocampus, amygdala, hypothala- mus, and frontal cortex (Weill-Engerer et al., 2002). Furthermore, although CRH induced an increase in plasma 5α3α-THPROG in patients suffering from Alzheimer’s disease, the neurosteroid lev- els remained signiﬁcantly lower than in control patients (Bernardi et al., 2000). Therefore, it is conceivable that neurosteroids may be less effective in mediating the physiological responses to stress in patients suffering from this disease and restoration of normal levels may prove therapeutically beneﬁcial. Chronic stress exposure not only induces remodeling of den- dritic architecture, but additionally alters synapse formation and the expression of various neurotransmitter receptors (Joels et al., 2007; McEwen, 2010). Given that endogenous neurosteroids, such as 5α3α-THPROG and 5α3α-THDOC, are such potent positive allosteric modulators of GABAAR function, and that GABAARs have such a prominent inﬂuence on the HPA axis, the impact that chronic stress has upon GABAAR-mediated inhibition within the brain is of particular interest. The majority of research has focused upon chronic stress-induced alterations in the excitatory neuro- transmitter systems, with relatively little attention being given to the GABAergic system. However, the expression of mRNAs encoding for certain GABAAR subunits was altered in the rat hippocampus following the chronic exposure to levels of corti- costerone achieved during stress (Orchinik et al., 1995), although the functional signiﬁcance of this altered expression remains unex- plored. The impact that stress has upon brain function (e.g., LTP) is dependent upon the level of glucocorticoid elevation and the dura- tion of the stressor exposure, in addition to the brain region under consideration (Lupien et al., 2009). Nevertheless, in chronically stressed rats, hippocampal LTP is difﬁcult to evoke (Alfarez et al., 2003) and this scenario can be mimicked in control non-stressed animals by the activation of glucocorticoid receptors (GRs), i.e., following 20 min pre-incubation of hippocampal slices in corticos- terone (100 nM; Alfarez et al., 2002). Whether this effect of chronic stress is associated with an altered expression of GABAARs as recently described for the hippocampus and mPFC of Alzheimer’s patients (Rissman et al., 2007; Luchetti et al., 2011), is not known. www.frontiersin.org December 2011 | Volume 5 | Article 131 | 7