Response of gonadotropin-releasing hormone neurons from female mice to dynamic-clamp-simulated GABAergic conductances across development and after prenatal androgenization

Abstract

Disrupted gonadotropin-releasing hormone (GnRH) secretion patterns can impair fertility as in polycystic ovary syndrome (PCOS).We used prenatally androgenized (PNA) female mice, which recapitulate neuroendocrine abnormalities observed in PCOS patients, to study how changes in GnRH neuron intrinsic properties during development (prepubertal 3-week-old versus adult females) and with PNA treatment shape their postsynaptic response to GABAergic input. The properties of isolated GABAergic postsynaptic currents in GnRH neurons were used to generate representative model conductances of 1, 2, 5, and 10 nS, with decay time constants representing prepubertal and adult mice (7 vs. 10 ms). These conductances were applied to GnRH neurons from each experimental group using dynamic clamp, and response was measured. Neither development nor PNA altered the response of GnRH neurons to small conductances (1 or 2 nS), and these conductances did not initiate action potentials. In response to the 5 nS conductance, dynamic-clamp-induced postsynaptic potentials were larger in 3-week-old controls versus 3-week-old PNA mice at the 7 ms decay time constant and larger than vehicle-treated (VEH) adults at the 10 ms decay time constant. In response to larger conductances, only seven of 78 GnRH neurons from adults generated action potentials, whereas 14 of 73 GnRH neurons from 3-week-old females did. Interestingly, an altered action potential waveform was observed only in 3-week-old PNA females. The changes in GnRH neuron intrinsic properties occurring with development and PNA treatment result in differential responses to the same physiologic GABA input and may contribute to the action potential firing changes previously reported in this model.

Keywords: GnRH; PCOS; dynamic clamp; GABA.