Robust GABAergic Regulation of the GnRH Neuron Distal Dendron

Xinhuai Liu, Robert Porteous, Allan E Herbison
Endocrinology, Volume 164, Issue 1, January 2023, bqac194
https://doi.org/10.1210/endocr/bqac194

Abstract

The amino acid transmitter γ-aminobutyric acid (GABA) is suspected to play an important role in regulating the activity of the gonadotropin-releasing hormone (GnRH) neurons controlling fertility. Rodent GnRH neurons have a novel dendritic compartment termed the “distal dendron” through which action potentials pass to the axon terminals and where inputs from the kisspeptin pulse generator drive pulsatile GnRH secretion. Combining Gnrh1-Cre mice with the Cre-dependent calcium sensor GCaMP6 and confocal imaging of acute brain slices, we examined whether GABA regulated intracellular calcium concentrations ([Ca²⁺]) in the GnRH neuron distal dendron. Short puffs of GABA on the dendron evoked either a monophasic sustained suppression of [Ca²⁺] or a biphasic acute elevation in [Ca²⁺] followed by the sustained suppression. Application of muscimol to the dendron replicated the acute elevation in [Ca²⁺] while baclofen generated the sustained suppression. Robust GABA_B receptor-mediated inhibition was observed in 80% to 100% of dendrons recorded from females across the estrous cycle and from approximately 70% of dendrons in males. In contrast, the GABA_A receptor–mediated excitation was rare in males and varied across the estrous cycle, being most prominent at proestrus. The activation of GABA_B receptors potently suppressed the stimulatory effect of kisspeptin on the dendron. These observations demonstrate that the great majority of GnRH neuron distal dendrons are regulated by GABAergic inputs in a sex- and estrous cycle–dependent manner, with robust GABA_B receptor-mediated inhibition being the primary mode of signaling. This provides a new, kisspeptin-independent, pathway for the regulation of pulsatile and surge modes of GnRH secretion in the rodent.

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