# Development of the GnRH neuronal network and effects of prenatal androgen exposure

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $429,969

## Abstract

Project Summary
Gonadotropin-releasing hormone (GnRH) neurons form the final common central pathway regulating fertility.
Properly patterned GnRH release is required for fertility and is often disrupted in women with polycystic ovary
syndrome (PCOS). Hyperandrogenic PCOS affects ~8-10% of women. In these women, there is a persistent
high frequency of luteinizing hormone (LH), and likely GnRH, release. Prenatally androgenized (PNA) mice
have neuroendocrine phenotypes similar to women with PCOS, including high LH pulse frequency, and can be
used to study mechanisms of this increase. Pathophysiology similar to PCOS is being detected at younger
ages, suggesting the antecedents of this disorder may be developmentally programmed. In the previous work
from a different funding mechanism (NCTRI), we characterized the development of GnRH neuron activity and
GABA transmission to these cells, showing that PNA disrupts both parameters before puberty, and that PNA-
induced changes before and after puberty are different. The neurobiological mechanisms underlying these
observations are largely unknown. Our working model to explain these findings is that 1) PNA alters the
biophysical properties of GnRH neurons and their afferents; 2) altered epigenetic programing at least in part
underlies these changes; 3) PNA increases excitatory GABA synaptic drive to GnRH neurons before puberty
and this increase continues in adults; 4) before puberty in PNA mice, GnRH neurons initiate intrinsic changes
to adapt to the increased GABA drive, and firing output is reduced; 5) developmental changes in PNA mice
lead to failure of these GnRH neuron adaptations, so that in PNA adults, increased GABA drive contributes to
increased GnRH neuron firing; 6) the increased neuroendocrine drive increases androgens, which are critical
to maintain neuroendocrine PNA phenotypes in adults. We will test this model in two aims. Aim 1 will identify
the mechanisms underlying prepubertal adaptation of GnRH neurons in PNA mice to increased GABA drive.
Aim 2 will characterize the epigenetic landscape in GnRH neurons during development, and changes induced
by PNA. The role of the ovary and androgen replacement in establishing and maintaining epigenetic changes
will also be assessed. Preliminary data indicate that GnRH neuron action potential firing, calcium currents and
potassium currents are all differentially regulated in prepubertal vs adult PNA mice compared to controls. To
complement the electrophysiology studies, we have adapted epigenetic profiling to libraries made from a few
hundred neurons and established fluorescent cell sorting protocols that yield sufficient numbers of enriched
GnRH neurons for these analyses. We are thus positioned to examine the molecular and biophysical
underpinnings of the functional changes of GnRH neurons observed in PNA mice. This work will provide
mechanistic insight currently lacking on the typical functional development of GnRH neurons through the
pubertal process...

## Key facts

- **NIH application ID:** 10768570
- **Project number:** 5R01HD104345-04
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Suzanne M MOENTER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $429,969
- **Award type:** 5
- **Project period:** 2021-05-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10768570

## Citation

> US National Institutes of Health, RePORTER application 10768570, Development of the GnRH neuronal network and effects of prenatal androgen exposure (5R01HD104345-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10768570. Licensed CC0.

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