Gonadal hormone‐independent sex differences in GABA A receptor activation in rat embryonic hypothalamic neurons

MIR, FRANCO R.; AGUAYO, LUIS G.; WILSON, CARLOS; CAMBIASSO, MARÍA JULIA; WILSON, CARLOS; CAMBIASSO, MARÍA JULIA; CABRERA ZAPATA, LUCAS E.; CABRERA ZAPATA, LUCAS E.; MIR, FRANCO R.; AGUAYO, LUIS G.

BRITISH JOURNAL OF PHARMACOLOGY

WILEY-BLACKWELL PUBLISHING, INC

Año: 2020 vol. 177 p. 3075 - 3090

0007-1188

Background and Purpose: GABAA receptor functions are dependent on subunit composition,and, through their activation, GABA can exert trophic actions in immatureneurons. Although several sex differences in GABA-mediated responses are knownto be dependent on gonadal hormones, few studies have dealt with sex differencesdetected before the critical period of brain masculinisation. In this study, we assessedGABAA receptor functionality in sexually segregated neurons before brain hormonalmasculinisation.Experimental Approach: Ventromedial hypothalamic neurons were obtained fromembryonic day 16 rat brains and grown in vitro for 2 days. Calcium imaging and electrophysiologyrecordings were carried out to assess GABAA receptor functionalparameters.Key Results: GABAA receptor activation elicited calcium entry in immature hypothalamicneurons mainly through L-type voltage-dependent calcium channels. Nifedipineblocked calcium entry more efficiently in male than in female neurons. There weremore male than female neurons responding to GABA, and they needed more time toreturn to resting levels. Pharmacological characterisation revealed that propofolenhanced GABAA-mediated currents and blunted GABA-mediated calcium entrymore efficiently in female neurons than in males. Testosterone treatment did noterase such sex differences. These data suggest sex differences in the expression ofGABAA receptor subtypes.Conclusion and Implications: GABA-mediated responses are sexually dimorphic evenin the absence of gonadal hormone influence, suggesting genetically biased differences.These results highlight the importance of GABAA receptors in hypothalamicneurons even before hormonal masculinisation of the brain.