Altered GABA_AReceptor-Mediated Synaptic Transmission Disrupts the Firing of Gonadotropin-Releasing Hormone Neurons in Male Mice under Conditions That Mimic Steroid Abuse

Abstract

Gonadotropin-releasing hormone (GnRH) neurons are the central regulators of reproduction. GABAergic transmission plays a critical role in pubertal activation of pulsatile GnRH secretion. Self-administration of excessive doses of anabolic androgenic steroids (AAS) disrupts reproductive function and may have critical repercussions for pubertal onset in adolescent users. Here, we demonstrate that chronic treatment of adolescent male mice with the AAS 17␣-methyltestosterone significantly decreased action potential frequency in GnRH neurons, reduced the serum gonadotropin levels, and decreased testes mass. AAS treatment did not induce significant changes in GABA A receptor subunit mRNA levels or alter the amplitude or decay kinetics of GABA A receptor-mediated spontaneous postsynaptic currents (sPSCs) or tonic currents in GnRH neurons. However, AAS treatment significantly increased action potential frequency in neighboring medial preoptic area (mPOA) neurons and GABA A receptor-mediated sPSC frequency in GnRH neurons. In addition, physical isolation of the more lateral aspects of the mPOA from the medially localized GnRH neurons abrogated the AAS-induced increase in GABA A receptor-mediated sPSC frequency and the decrease in action potential firing in the GnRH cells. Our results indicate that AAS act predominantly on steroid-sensitive presynaptic neurons within the mPOA to impart significant increases in GABA A receptormediated inhibitory tone onto downstream GnRH neurons, resulting in diminished activity of these pivotal mediators of reproductive function. These AAS-induced changes in central GABAergic circuits of the forebrain may significantly contribute to the disruptive actions of these drugs on pubertal maturation and the development of reproductive competence in male steroid abusers.

The Buzz about Anabolic Androgenic Steroids: Electrophysiological Effects in Excitable Tissues

“…AAS treatment had no direct effect on the expression of GABA A receptor subunit mRNAs in identified GnRH neurons, nor did treatment alter the amplitude or decay kinetics of GABA A receptor-mediated spontaneous postsynaptic currents (sPSCs), miniature sPSCs or tonic currents in these cells. These data indicate that AAS treatment was without an appreciable effect on the complement or function of postsynaptic GABA A receptors expressed in GnRH neurons (61, 62). However, treatment did result in a significant increase in the frequency of sPSCs onto GnRH neurons in both sexes, consistent with a significant effect of AAS exposure on neurons that provide afferent GABAergic innervation to the GnRH cells.…”

“…In both sexes, interference with peripheral reproductive state was found to be accompanied by significant decreases in the frequency of action potentials in gonadotropin releasing hormone (GnRH) neurons (61, 62); neurons that mediate the final control over the hypothalamic/pituitary/gonadal (HPG) axis (56). AAS treatment had no direct effect on the expression of GABA A receptor subunit mRNAs in identified GnRH neurons, nor did treatment alter the amplitude or decay kinetics of GABA A receptor-mediated spontaneous postsynaptic currents (sPSCs), miniature sPSCs or tonic currents in these cells.…”

“…However, treatment did result in a significant increase in the frequency of sPSCs onto GnRH neurons in both sexes, consistent with a significant effect of AAS exposure on neurons that provide afferent GABAergic innervation to the GnRH cells. In male mice, this increase in sPSC frequency could be attributed to augmented activity of presynaptic GABAergic neurons within the medial preoptic area (mPOA) (61). While studies in female mice also demonstrated significant effects of chronic exposure to 17α-MeT on the activity of neurons within the mPOA, the actions were not correlated with concomitant changes in GnRH neuronal activity.…”

Frequency-Dependent Recruitment of Fast Amino Acid and Slow Neuropeptide Neurotransmitter Release Controls Gonadotropin-Releasing Hormone Neuron Excitability

“…2 E1), and stimulation was applied at the same parameters used for the AVPV. The LPOA has recently been shown to provide a GABAergic input to GnRH neurons (Penatti et al, 2010). While stimulation of the LPOA was found to activate currents in GnRH neurons, these were much smaller in amplitude than that observed following AVPV stimulation (mean current amplitude 19 Ϯ 8 pA for LPOA vs 169 Ϯ 10 pA for AVPV; Fig.…”

Maternal Dexamethasone Exposure Alters Synaptic Inputs to Gonadotropin-Releasing Hormone Neurons in the Early Postnatal Rat

“…Synaptic and extrasynaptic GABA A receptors on GnRH neurons are regulated by neurosteroids and androgen, to suppress the downstream firing of GnRH neurons (79, 80). Thus, the decrease in synaptic inputs by prenatal DEX exposure could affect synaptic transmission to GnRH neurons in the adult stages.…”