**8. DS1, a δ-subunit-containing GABAA receptor agonist, reduces GnRH mRNA expression and increases that of GnRHR in GT1-7 cells**

It is well documented that the neurotransmitter γ-aminobutyric acid (GABA) can modulate the activity of GnRH neurons. GnRH neurons possess functional GABAA receptors [34], and GABAergic neurons establish synapses with GnRH neurons [35]. GABA neurons predominantly exert their inhibitory effect on GnRH neurons in rodents and sheep. GT1-7 cells also express functional GABAA receptors [36]. GABAA receptors are multimeric proteins that are composed of five subunits drawn from a repertoire of several homologous protein groups (α1-6, β1-3, γ1-3, δ, ε, θ, and π); the majority of GABAA receptors in the central nervous system are composed of α, β, and γ subunits, and less abundant populations of GABA<sup>A</sup> receptor contain the δ subunit [37]. DS1, an α4β3δ GABAA receptor agonist, reduces GnRH mRNA expression in GT1-7 cells, although DS1 can exert a stimulatory effect on signal transduction systems, such as ERK and cAMP/PKA [38]. The δ-subunit-containing α4β3δ GABA<sup>A</sup> receptor was found in extra-synaptic sites and is known to control neuronal excitability [39]. Interestingly, although GnRH mRNA expression was decreased, GnRHR expression within GT1-7 cells was significantly increased by DS1 stimulation [38] (**Figure 1**). At present, it is still unknown why δ-subunit-containing GABAA receptor agonism decreases the production of GnRH in spite of increasing GnRHR expression. We currently speculate that GABA could modulate GnRH-producing neurons through δ-containing GABAA receptors and deplete their GnRH content by modulating gene expression and secretory function in association with the expression of their GnRHR within the cell (**Figure 1**).
