Development of GABA Inputs to Gonadotropin-Releasing Hormone (GnRH) Neurons and Effects of Prenatal Androgen Exposure
Berg, Tova
2020
Abstract
Polycystic ovary syndrome (PCOS) is a leading cause of infertility and is characterized by hyperandrogenemia, polycystic ovaries and irregular menses. The underlying cause of PCOS is unknown but may involve effects of androgens during prenatal development. Women with hyperandrogenemia during pregnancy have daughters at higher risk of developing PCOS as adults. Androgens may interfere with development of neuronal networks important for regulating reproduction. Gonadotropin-releasing hormone (GnRH) neurons are the final common pathway for the central regulation of fertility. Pulsatile GnRH release signals the pituitary to release luteinizing hormone (LH) which stimulates ovarian hormone production. In most women with PCOS, GnRH/LH pulse frequency is persistently elevated, contributing to excess ovarian androgen production and irregular cycles. Clinical studies have revealed that obese peripubertal girls with hyperandrogenemia have elevated LH pulse frequency suggesting that neuroendocrine dysfunction seen in adult women with PCOS emerges during prepubertal development. Prenatal androgen (PNA) exposure has been used in experimental models to replicate aspects of PCOS in adulthood. GnRH neurons from adult PNA mice have increased firing rate and increased excitatory GABAergic transmission. GABAergic afferents are a major source of input to GnRH neurons but neither the typical pattern of when GABAergic transmission develops nor when changes emerge with PNA are understood. We used whole-cell voltage clamp recordings to examine GABAergic postsynaptic currents (PSCs) in GnRH neurons from control and PNA mice during postnatal development in both females and males. 1-wk old female and male mice had low frequencies of GABAergic transmission that increased to adult levels by 3- and 4-wks of age, respectively. This increase was more robust in PNA mice of both sexes. This difference persisted into adulthood in females but not males. Differences in PSC frequency were activity independent, consistent with changes in synaptic connectivity rather than presynaptic activation. In PNA females, increased GABAergic transmission occurs concomitantly with decreased GnRH neuron firing at 3-wks of age. The percentage of cells firing and membrane potential depolarization in response to GABA was decreased in PNA females at 3-wks of age but not adults. This difference was not due to altered chloride homeostasis of GnRH neurons as the equilibrium potential of the GABAAR-mediated current was not altered by PNA at 3-wks of age. Our work shows that prenatal androgen exposure programs neuroendocrine changes that may contribute to adult reproductive dysfunction. Increasing numbers of pre-adolescents are at risk for developing hyperandrogenemia in association with childhood obesity, highlighting our need for greater understanding of how excess androgen exposure affects deveSubjects
Development of GABA Inputs to Gonadotropin-Releasing Hormone (GnRH) Neurons and Effects of Prenatal Androgen Exposure
Types
Thesis
Metadata
Show full item recordCollections
Remediation of Harmful Language
The University of Michigan Library aims to describe library materials in a way that respects the people and communities who create, use, and are represented in our collections. Report harmful or offensive language in catalog records, finding aids, or elsewhere in our collections anonymously through our metadata feedback form. More information at Remediation of Harmful Language.
Accessibility
If you are unable to use this file in its current format, please select the Contact Us link and we can modify it to make it more accessible to you.