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 is 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.

Figure 1. GABA_AR plasticity over the estrous cycle, puberty, and pregnancy

The diagram summarizes changes in GABA_AR δ subunit expression relative to changes in neurosteroid levels over the estrous cycle (a), puberty (b), and throughout pregnancy and the postpartum period (c). This figure summarizes data obtained from (Griffiths and Lovick 2005a; Griffiths and Lovick 2005b; Maguire et al. 2009; Maguire and Mody 2008; Maguire et al. 2005; Wu et al. 2013).