Endogenous Activation of Metabotropic Glutamate Receptors Modulates GABAergic Transmission to Gonadotropin-Releasing Hormone Neurons and Alters Their Firing Rate: A Possible Local Feedback Circuit

Abstract

Gonadotropin-releasing hormone (GnRH) neurons are the primary central regulators of fertility, receiving input from GABAergic afferents via GABA(A) receptors. We tested whether metabotropic glutamate receptors (mGluRs) regulate GABA transmission to GnRH neurons and GnRH neuronal firing pattern. Whole-cell recordings were performed under conditions isolating ionotropic GABA postsynaptic currents (PSCs) in brain slices. The broad-spectrum mGluR agonist 1-aminocyclopentane-1,3-dicarboxylic acid (ACPD) decreased the frequency of GABA(A)-mediated spontaneous PSCs in a reversible manner. Amplitude and kinetics were not altered, suggesting that afferent GABA neurons are the primary targets. TTX eliminated the effects of ACPD in most tested neurons. Group II [2-(2,3-dicarboxycyclopropyl) glycine] and III (L-AP-4) mGluR agonists mediated this response; a group I agonist (3,5-dihydroxyphenylglycine) was not effective. The broad-spectrum antagonist alpha-methyl-4-carboxyphenylglycine (MCPG) and/or (RS)-alpha-cyclopropyl-4-phosphonophenylglycine (CPPG) (group III antagonist) enhanced spontaneous PSC frequency, particularly when initial frequency was low, suggesting that endogenous activation of mGluRs regulates GABA transmission to GnRH neurons. Extracellular recordings were used to evaluate GnRH neuron firing rate within the network. ACPD reduced firing rate, and MCPG plus CPPG had an opposite effect, indicating that mGluRs help control excitability of the GnRH network. GnRH neurons express vesicular glutamate transporters, suggesting they may corelease this transmitter. Simulation of firing activity in a GnRH neuron decreased PSC frequency in that cell, an effect blocked by antagonism of mGluRs but not GnRH receptors. These results demonstrate an inhibition of GABAergic inputs to GnRH neurons by mGluRs via a presynaptic mechanism. Through this mechanism, local glutamate milieu, possibly contributed by GnRH neurons themselves, plays an important role in modulating GnRH release and the central regulation of fertility.