Effects of development and prenatal androgen exposure on GnRH neuron intrinsic properties

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Project Summary Gonadotropin-releasing hormone (GnRH) neurons form the final central pathway for the control of reproductive function, releasing GnRH in a pulsatile manner. Low frequency GnRH pulses favor the secretion of follicle- stimulating hormone (FSH), whereas high frequency GnRH pulses favor the secretion of luteinizing hormone (LH). Disruptions to the secretory patterns of these hormones can result in subfertility or infertility. Polycystic ovary syndrome (PCOS), and in particular hyperandrogenemic PCOS, is a disorder in which disruptions to these hormone release patterns result in impaired fertility. Specifically, sustained high frequency LH, and presumably GnRH, pulses are a hallmark of hyperandrogenemic PCOS. To study neuroendocrine aspects that may contribute to this disorder, the proposed work uses a prenatally androgenized (PNA) mouse model. PNA mice recapitulate many neuroendocrine phenotypes reported in women with hyperandrogenemic PCOS, including disrupted reproductive cycles, elevated LH-pulse frequency and increased testosterone. Studies of GFP-identified GnRH neurons from three-week-old PNA females revealed that action potential firing activity is lower than in cells from controls. In contrast, GnRH neuron activity is increased in cells from adult PNA mice relative to controls. This was a curious observation as GABAergic transmission, which is excitatory in GnRH neurons, was increased at both of these developmental timepoints. In 3-wk old PNA females, GnRH neurons have a reduced firing response to local GABA application compared to controls, but there is no change in either reversal potential for current through the GABAA receptor or in the basal membrane potential of these cells. Together these observations suggest the postulate that changes occur in voltage-gated channels of GnRH neurons from PNA mice to compensate for increased excitatory synaptic input in young mice but that these changes are not maintained in adults, leading to hyperactivity. My early data indicate that GnRH neuron excitability and action potential characteristics can be similar among the groups, but have different underlying ionic conductance characteristics as a result of development and PNA treatment. The first aim of this project tests how voltage-gated potassium (K+) currents, which play a large role in how neurons respond to synaptic inputs and generate action potentials, are altered among these groups. Our findings we be used to generate computational models of potassium currents that will assist in this interpretation The second aim will use dynamic clamp to test if GnRH neurons from control vs PNA mice respond differently to representative trains of simulated GABA conductances from our previous work and/or current injection. We will also test how modelled potassium currents interact with the native milieu of recorded GnRH neurons to account for differences in response. Completion of this project will provide insight into the intrinsic properties of GnRH neurons, how these change during typical development and with PNA treatment, potentially providing insight into the etiology of PCOS and providing me with the training required to successfully become an independent scientist.