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 ␣-methyl-4-carboxyphenylglycine (MCPG) and/or (RS)-␣-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.

Initiation and Propagation of Action Potentials in Gonadotropin-Releasing Hormone Neuron Dendrites

“…Ca 2ϩ signaling in the soma of GnRH neurons has been proposed to regulate burst firing through the opening of Ca 2ϩ -activated K ϩ channels (Lee et al, 2010). This may also occur in the dendrite; however, dendritic Ca 2ϩ rises could also drive the release of dendritic messengers (Chu and Moenter, 2005). As the dendrites of GnRH neurons bundle with one another (Campbell et al, 2009), dendritic transmitter release may facilitate synchro- Dual on-cell recordings were performed from the soma and dendrite of a GnRH neuron.…”

Endogenous mGluR Activity Suppresses GABAergic Transmission in Avian Cochlear Nucleus Magnocellularis Neurons

“…Modulation of the frequency but not the amplitude of mIPSCs would imply a presynaptic mechanism, modulation of the amplitude but not of the frequency of mIPSCs would imply a postsynaptic mechanism, and modulation of both the frequency and the amplitude of mIPSCs would imply a mechanism involving both pre-and postsynaptic elements of the synapse (e.g., Chu and Moenter 2005;Piet et al 2003;Valenti et al 2003). A lack of changes in the frequency and the amplitude of mIPSCs by a drug, however, does not necessarily exclude presynaptic modulation because some drugs may influence transmission by inhibiting voltage-gated Ca 2ϩ channels on presynaptic terminals, without affecting Ca 2ϩ and action potential-independent release of neurotransmitters (e.g., Gereau and Conn 1995).…”

GABARAPL1 (GEC1): Original or copycat?

“…43 Three FoxO target consensus sequences are located upstream of the promoter region in the mouse Gabarapl1 gene 44 and and glutamate receptors, respectively. 31,32 As an estrogen-regulated gene, Gabarapl1 may play a role in the responsiveness of GnRH neurons to estrogen through its implication in GABA A R trafficking to the plasma membrane.…”