National Centers for Translational Research in Reproduction and Infertility

Development of the GnRH Neuronal Network and the Effects of Prenatal Androgens

University of Michigan

PI:  S. M. Moenter

Gonadotropin-releasing hormone (GnRH) neurons form the final common central pathway regulating fertility. Properly patterned GnRH release is absolutely required for fertility, but is often disrupted in women with polycystic ovary syndrome (PCOS). PCOS affects – 8% of women. In most women with PCOS, there is a persistent high frequency of LH release reflecting high frequency GnRH release. Prenatally androgenized (PNA) mice have neuroendocrine phenotypes similar to women with PCOS, including increased GnRH neuron activity, allowing mechanisms of this increase to be studied. PCOS is being detected at younger ages, suggesting the antecedents of this disorder may be developmentally programmed. The neurobiological changes underiying increased GnRH activity in this disorder and when during development changes occur are largely unknown. The working hypothesis is that GnRH neuron activity during the prepubertal period is critical for attracting appropriate afferent inputs and that alterations in GnRH neuron activity during this time period that are induced by PNA alter the adult wiring and function of the GnRH neuronal circuitry. We will test this hypothesis in two aims using state-of-the-art electrophysiology, defined animal models, and cell-targeted genetic tools to elucidate the molecular and physiologic changes that occur. Aim 1 will characterize postnatal development of the GnRH neuronal network and the effects of prenatal androgen exposure. Aim 2 will determine the role of GnRH neuron activity before puberty in establishing the adult network. Preliminary data indicate that GnRH neuron action potential firing and GnRH release are increased during the juvenile period in PNA vs. control mice. Neuronal activity during development is important for establishing appropriate synaptic interactions. Consistent with this, there is increased fast synaptic input to GnRH neurons at two weeks of age in PNA mice. We will characterize the normal development of GnRH neuron activity, release, pattern of fast synaptic input, response to inhibitory and excitatory neuromodulators, and pituitary responsiveness. We will then manipulate GnRH neuron activity in vivo during the neonatal/juvenile period by targeting inhibitory designer receptors exclusively activated by designer drugs (DREADDs) to GnRH neurons using cre-lox technology to determine the role of GnRH neuron activity in establishing these parameters. To complement the electrophysiology studies, we have adapted an innovative method for cell type-specific translating mRNA enrichment to examine the molecular underpinnings of the functional changes observed in PNA mice at the level of the GnRH neuron.