Chemogenetic Suppression of GnRH Neurons during Pubertal Development Can Alter Adult GnRH Neuron Firing Rate and Reproductive Parameters in Female Mice

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Gonadotropin-releasing hormone (GnRH) neurons control anterior pituitary, and thereby gonadal function. GnRH neurons are active before outward indicators of puberty appear. Prenatal androgen (PNA) exposure mimics reproductive dysfunction of the common fertility disorder polycystic ovary syndrome (PCOS) and reduces prepubertal GnRH neuron activity. Early neuron activity can play a critical role in establishing circuitry and adult function. We tested the hypothesis that changing prepubertal GnRH neuron activity programs adult GnRH neuron activity and reproduction independent of androgen exposure in female mice. Activating (3Dq) or inhibitory (4Di) designer receptors exclusively activated by designer drugs (DREADDs) were targeted to GnRH neurons using Cre-lox technology. In control studies, the DREADD ligand clozapine n-oxide (CNO) produced the expected changes in GnRH neuron activity in vitro and luteinizing hormone (LH) release in vivo. CNO was administered to control or PNA mice between two and three weeks of age, when GnRH neuron firing rate is reduced in PNA mice. In controls, reducing prepubertal GnRH neuron activity with 4Di increased adult GnRH neuron firing rate and days in diestrus but did not change puberty onset or GABA transmission to these cells. In contrast, activating GnRH neurons had no effect on reproductive parameters or firing rate and did not rescue reproductive phenotypes in PNA mice. These studies support the hypothesis that prepubertal neuronal activity sculpts elements of the adult reproductive neuroendocrine axis and cyclicity but indicate that other PNA-induced programming actions are required for full reproductive phenotypes and/or that compensatory mechanisms overcome activity-mediated changes to mitigate reproductive changes in adults.

Significance Statement Gonadotropin-releasing hormone (GnRH) neuron activity and associated GnRH release link the neuronal control of reproduction to peripheral secretion of reproductive hormones. Prenatally androgenized (PNA) mice mimic neuroendocrine aspects of polycystic ovary syndrome (PCOS). PNA reduces prepubertal GnRH neuron activity but increases adult activity. Here, we reveal that prepubertal suppression of GnRH neuron activity without androgen exposure leads to similar increases in adult GnRH neuron activity, and a mild degradation in reproductive cycles. Increasing GnRH neuron activity before puberty, however, fails to rescue cycles in PNA mice. This provides a clearer understanding of the role prepubertal GnRH neuron activity plays in establishing adult reproductive function and suggests additional androgen-dependent programming actions are required for complete reproductive disruption in this model and perhaps PCOS.

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