Endocannabinoids and prostaglandins both contribute to GnRH neuron-GABAergic afferent local feedback circuits

Abstract

Gonadotropin-releasing hormone (GnRH) neurons form the final common pathway for central control of fertility. Regulation of GnRH neurons by long-loop gonadal steroid feedback through steroid receptor-expressing afferents such as GABAergic neurons is well studied. Recently, local central feedback circuits regulating GnRH neurons were identified. GnRH neuronal depolarization induces short-term inhibition of their GABAergic afferents via a mechanism dependent on metabotropic glutamate receptor (mGluR) activation. GnRH neurons are enveloped in astrocytes, which express mGluRs. GnRH neurons also produce endocannabinoids, which can be induced by mGluR activation. We hypothesized the local GnRH-GABA circuit utilizes glia-derived and/or cannabinoid mechanisms and is altered by steroid milieu. Whole cell voltage-clamp was used to record GABAergic postsynaptic currents (PSCs) from GnRH neurons before and after action potential-like depolarizations were mimicked. In GnRH neurons from ovariectomized (OVX) mice, this depolarization reduced PSC frequency. This suppression was blocked by inhibition of prostaglandin synthesis with indomethacin, by a prostaglandin receptor antagonist, or by a specific glial metabolic poison, together suggesting the postulate that prostaglandins, potentially glia-derived, play a role in this circuit. This circuit was also inhibited by a CB1 receptor antagonist or by blockade of endocannabinoid synthesis in GnRH neurons, suggesting an endocannabinoid element, as well. In females, local circuit inhibition persisted in androgen-treated mice but not in estradiol-treated mice or young ovary-intact mice. In contrast, local circuit inhibition was present in gonad-intact males. These data suggest GnRH neurons interact with their afferent neurons using multiple mechanisms and that these local circuits can be modified by both sex and steroid feedback.

Role of Glia in the Regulation of Gonadotropin-Releasing Hormone Neuronal Activity and Secretion

“…Astrocyte-derived PGE2 activates EP2 receptors (EP2) and the subsequent mobilization of a cAMP/PKA pathway in GnRH neurons, leading to the activation of a nonselective cation current that promotes membrane depolarization and initiates spike firing [44]. Moreover, the depolarization of GnRH neurons induces the short-term inhibition of their GABAergic afferents via a local feedback circuit that requires the presence of astrocyte-derived PGE2 [47]. Astrocytes also release TGFβs [39,48,49,50,51], which activate type I (TGFβ-RI) and type II (TGFβ-RII) serine/threonine kinase TGFβ receptors located on GnRH neuronal cell bodies [58,59].…”

“…These results thus identify PGE2 as a novel gliotransmitter, and point to astrocytes as important regulators of GnRH neuronal excitability. Moreover, astrocytic-derived PGE2 has recently been implicated in the regulation of a local feedback circuit involving GnRH neurons and their GABAergic afferents [47]. However, how the glial modulation of GnRH neuronal electrical activity affects neuropeptide secretion at their nerve endings is still unknown.…”

Endocannabinoids and Kisspeptins: Two Modulators in Fight for the Regulation of GnRH Activity

“…ECB biosynthesis in GnRH secreting neurons might be induced by the activation of metabotropic glutamate receptor (mGluR) located on astrocytes. In fact, in female mice, a complementary hypothesis suggests that local GnRH-GABA circuits uses just the glia derived prostaglandins and/or ECBs in a steroid dependent fashion (Glanowska & Moenter, 2011). GnRH neurons interact with their afferent neurons using several mechanisms and these local circuits can be modified by both sex and steroid feedback.…”

“…The inhibitory effect of AEA on GnRH-secreting neurons is reversed by estrogens (Scorticati et al, 2004), through the inhibition of astrocyte mGluR. Such a process inhibits prostaglandin mediated release of ECBs from GnRH secreting neurons (Glanowska & Moenter, 2011). Alternatively, estradiol might directly prevent the ECB mediated inhibition of GABA neurons (Glanowska & Moenter, 2011).…”

“…Such a process inhibits prostaglandin mediated release of ECBs from GnRH secreting neurons (Glanowska & Moenter, 2011). Alternatively, estradiol might directly prevent the ECB mediated inhibition of GABA neurons (Glanowska & Moenter, 2011). In the brain, functional relationships between CB1 and FAAH emerged, since they have a quite overlapping localization (Egertovà et al, 1998).…”