The role of ovarian hormone-derived neurosteroids on the regulation of GABAA receptors in affective disorders

Abstract

Rationale Neuroactive derivatives of steroid hormones, neurosteroids, can act on GABAA receptors (GABAARs) to potentiate the effects of GABA on these receptors. Neurosteroids become elevated to physiologically relevant levels under conditions characterized by increased steroid hormones. There is considerable evidence for plasticity of GABAARs associated with altered levels of neurosteroids which may counteract the fluctuations in the levels of these allosteric modulators. Objectives The objective of this review is to summarize the current literature on GABAAR plasticity under conditions characterized by alterations in neurosteroid levels, such as over the estrous cycle, during puberty, and throughout pregnancy and the postpartum period. Results The expression of specific GABAAR subunits are altered over the estrous cycle, at puberty, and throughout pregnancy and the postpartum period. Inability to regulate δ subunit-containing GABAARs throughout pregnancy and the postpartum period is associated with depression-like behavior restricted to the postpartum period. Conclusions GABAAR plasticity associated with alterations in neurosteroid levels represents a homeostatic compensatory mechanism to maintain an ideal level of inhibition to offset the potentiating effects of neurosteroids on GABAergic inhibition. Failure to properly regulate GABAARs under conditions of altered neurosteroid levels may increase vulnerability to mood disorders, such as premenstrual syndrome (PMS), premenstrual dysphoric disorder (PMDD), and postpartum depression.

GABAergic Control of Depression-Related Brain States

“…Maguire & Mody, 2007, 2008; J. L. Maguire, Stell, Rafizadeh, & Mody, 2005) (reviewed in MacKenzie & Maguire, 2014). …”

“…GABA sets the tempo of brain development, particularly in the cortex and hippocampus (reviewd in Ben-Ari, 2013; Ge et al, 2007). Its function through GABA A Rs is subject to direct modulation by neurosteroids (reviewed in Comenencia-Ortiz, Moss, & Davies, 2014; Gunn et al, 2014; MacKenzie & Maguire, 2014), and the function of GABA A Rs itself is vulnerable to environmental effects on E Cl (Ben-Ari, Khalilov, Kahle, & Cherubini, 2012). The collective evidence suggests that defects in GABergic transmission are causative rather than a consequence of pathological changes in glutamatergic tansmission.…”

Ovarian Hormone Fluctuation, Neurosteroids, and HPA Axis Dysregulation in Perimenopausal Depression: A Novel Heuristic Model

“…Which subunits a receptor contains will greatly influence its sensitivity to neurosteroids (see (59) for review). For example, the δ subunit has been shown to greatly increase receptor sensitivity to very low concentrations of neurosteroids; mice lacking the δ subunit therefore exhibit greatly reduced neurosteroid sensitivity (60).…”

5-HT1A receptors of the prelimbic cortex mediate the hormonal impact on learned fear expression in high-anxious female rats

“…Also, ovarian hormone fluctuations can greatly influence anxiety in humans (Arpels, 1996), as well as the expression of anxietyrelated behavior in rodents (Lund et al, 2005;Mora et al, 1996). As shown by neurochemical and electrophysiological studies, changes related to the estrous cycle seem to involve the functioning of the GABA (Mackenzie and Maguire, 2014;Pericic et al, 1986) and 5-HT brain systems (Williams and Uphouse, 1989), among others. Both neurotransmitters are actively implicated in the control of anxiety (Griebel and Holmes, 2013).…”