Estradiol Induces Diurnal Shifts in GABA Transmission to Gonadotropin-Releasing Hormone Neurons to Provide a Neural Signal for Ovulation

Abstract

Ovulation is initiated by a surge of gonadotropin-releasing hormone (GnRH) secretion by the brain. GnRH is normally under negative feedback control by ovarian steroids. During sustained exposure to estradiol in the late follicular phase of the reproductive cycle, however, the feedback action of this steroid switches to positive, inducing the surge. Here, we used an established ovariectomized, estradiol-treated (OVXϩE) mouse model exhibiting daily surges to investigate the neurobiological mechanisms underlying this switch. Specifically, we examined changes in GABA transmission to GnRH neurons, which can be excited by GABA A receptor activation. Spontaneous GABAergic postsynaptic currents (PSCs) were recorded in GnRH neurons from OVXϩE and OVX mice in coronal and sagittal slices. There were no diurnal changes in PSC frequency in cells from OVX mice in either slice orientation. In OVXϩE cells in both orientations, PSC frequency was low during negative feedback but increased at surge onset. During the surge peak, this increase subsided in coronal slices but persisted in sagittal slices. Comparison of PSCs before and during tetrodotoxin (TTX) treatment showed TTX decreased PSC frequency in OVXϩE cells in sagittal slices, but not coronal slices. This indicates estradiol acts on multiple GABAergic afferent populations to increase transmission through both activity-dependent and -independent mechanisms. Estradiol also increased PSC amplitude during the surge. Estradiol and the diurnal cycle thus interact to induce shifts in both GABA transmission and postsynaptic response that would produce appropriate changes in GnRH neuron firing activity and hormone release.

Membrane-initiated estrogen signaling in hypothalamic neurons

“…The positive feedback is believed to be by an action of E2 in the anteroventral periventricular (AVPV) nucleus (Herbison, 1998, Han et al, 2005, Smith et al, 2006, Wintermantel et al, 2006. Neurons in the AVPV express kisspeptin, a neuropeptide encoded by the Kiss gene, GABA and opioid peptides, all of which are important for regulation of GnRH neurosecretion (Simerly et al, 1988, Wagner et al, 2001a, Jackson and Kuehl, 2002, DeFazio et al, 2002, Smith et al, 2006, Christian and Moenter, 2007. The AVPV area expresses high levels of ERα and also ERβ, and the actions of the gonadal steroids are mediated, in part, via the nuclearinitiated signaling (genomic) mechanism (Shughrue et al, 1997, Wintermantel et al, 2006.…”

Hypothalamic gonadotropin-releasing hormone (GnRH) receptor neurons fire in synchrony with the female reproductive cycle

“…2F), suggesting that decreased GnRH release due to estradiol alleviates GnRHR neuronal burst activity. The direct effect of the estradiol-generated tonicity of GnRHR neuron firing could result from the prevention of intrinsic cascades known to induce oscillatory spike behavior (Bal et al 1995;Chu et al 2010) or by the modulation of local network activity by estradiol (Christian and Moenter 2007;Veliskova and Velisek 2007). Estradiol is well known as an initiator of burst activity (Abe and Terasawa 2005;Chu et al 2009), but such a scenario seems unlikely here.…”

Role of Kisspeptine in Regulation of Reproductive Function

“…если ГнРГ-нейроны сами экспрессируют ER, очевидно, что регулирующее действие эстра-диола на ГнРГ-нейроны может быть трансси-наптическим потому, что эстрадиол регулиру-ет синаптическую передачу к этим клеткам [44] и нейроны, которые считаются афферентными к ГнРГ-нейронам, экспрессируют как ER-α, так и ER-β [45][46][47][48]. Особый интерес вызывают последние ис-следования, посвященные нейромодулятору кисспептину, о возможности действия эстра-диола по механизму обратной связи при регу-ляции ГнРГ-нейронов [9,49,50].…”

“…Интересно от-метить, что некоторые пациенты с идиопати-ческим ИГГ отвечают на введение экзогенного ГнРГ, что свидетельствует о том, что дефект мо-жет быть в нарушении синтеза ГнРГ, секреции или его активности [52]. Как и кисспептин, так и рецептор кисспептина широко экспрессиру-ются в гипоталамусе [11,22,50,53], в областях, регулирующих нейрональную активность ГнРГ [44,50], и ГнРГ-нейроны экспрессируют GPR54 [3][4][5][6]. Кисспептин усиливает выброс ГнРГ и ЛГ и усиливает активность ГнРГ-нейронов [5,6,[55][56][57][58].…”