Steroid modulation of GABAA receptor-mediated transmission in the hypothalamus: effects on reproductive function

Abstract

The hypothalamus, the seat of neuroendocrine control, is exquisitely sensitive to gonadal steroids. For decades it has been known that androgens, estrogens and progestins, acting through nuclear hormone receptors, elicit both organizational and activational effects in the hypothalamus and basal forebrain that are essential for reproductive function. While changes in gene expression mediated by these classical hormone pathways are paramount in governing both sexual differentiation and the neural control of reproduction, it is also clear that steroids impart critical control of neuroendocrine functions through non-genomic mechanisms. Specifically, endogenous neurosteroid derivatives of deoxycorticosterone, progesterone and testosterone, as well and synthetic anabolic androgenic steroids that are self-administered as drugs of abuse, elicit acute effects via allosteric modulation of gamma-aminobutyric acid type A receptors. GABAergic transmission within the hypothalamus and basal forebrain is a key regulator of pubertal onset, the expression of sexual behaviors, pregnancy and parturition. Summarized here are the known actions of steroid modulators on GABAergic transmission within the hypothalamus/basal forebrain, with a focus on the medial preoptic area and the supraoptic/paraventricular nuclei that are known to be central players in the control of reproduction.

Figure 1

Representative steroid modulators of the GABA_A receptor for A) the positive neurosteroids: allopregnanolone, b) the negative neurosteroids: pregnenolone sulfate, C) the AAS: 17α-methyltestosterone and D) pheromones: androstenol. Structures are from the ChemIDplus website: http://chem.sis.nlm.nih.gov/chemidplus/.

Figure 2. Anatomical correlates of female reproductive behaviors

Schematic representation of a midline-sagittal section and hypothalamic/basal forebrain or downstream midbrain regions in which GABAergic transmission facilitates (green) or antagonize (red) lordosis in rodents. mPOA: medial preoptic nucleus, VMN: ventromedial nucleus of the hypothalamus, VTA: ventral tegmental area, MCG: midbrain central gray; cc: corpus callosum.

Figure 3

(A) Levels of ε subunit mRNA in the mPOA as assessed by standard semi-quantitative RT-PCR. Data are normalized to values from adult, gonadally-intact C57Bl/6 males (100%). (B) Percent potentiation in average peak current (I_peak) over control elicited by 3α-diol.

Figure 4

A) Representative micrograph of an acutely isolated slice from a female mouse at the level of the mPOA and a patch electrode. B) Micrograph of the mPOA processed for synaptophysin immunocytochemistry (red) from the transgenic line of mice in which GFP is expressed in GnRH neurons (green) amidst a number of non-GnRH cell bodies (black). Mice were kindly provided by Dr. Sue Moenter (University of Virginia). C) Representative sIPSCs recorded from an identified GFP-GnRH neuron demonstrating reversible potentiation (left) and inhibition (right) of peak current amplitude by 1 μM 17α-MeT. D) Representative whole-cell currents recorded in the absence of GABA from an acutely dissociated GFP-GnRH neuron. Left: current arising from spontaneously active GABA_A receptors. No exogenous GABA was applied; spontaneous current is antagonized by the noncompetitive GABA_A receptor antagonist, picrotoxin. Right: spontaneous current from the same GFP-GnRH neuron demonstrating reversible inhibition by a maximally effective (10 μM) concentration of 17α-MeT. V3: Third Ventricle. Data are courtesy of Dr. Carlos Penatti, Dr. Brian Jones and Ms. Sandra Pahl.