Kisspeptin Increases Gonadotropin-Releasing Hormone (GnRH) Neuron Excitability
Presentation Number: OR19-1
Date of Presentation: April 4th, 2017
Caroline Elizabeth Adams*, Santiago Schnell and Suzanne M Moenter
University of Michigan, MI
GnRH neurons form the final common pathway for neural control of fertility. A surge of GnRH release initiates a surge of luteinizing hormone (LH) secretion to trigger ovulation. The GnRH surge is initiated when estradiol switches from negative feedback, suppressing GnRH action potential firing, to positive feedback increasing firing. In rodents, this switch is time-of-day dependent. In ovariectomized mice implanted with estradiol (OVX+E), GnRH neuron firing rates and LH release are suppressed in the morning (AM) by negative feedback (-FB) and elevated in the afternoon (PM) by positive feedback (+FB). No time-of-day dependent shift is observed in OVX mice. Most estradiol feedback effects are transmitted indirectly to GnRH neurons as they do not express detectable estrogen receptor α, which is required for feedback. Kisspeptin is produced by estradiol-sensitive GnRH afferents in the anteroventral periventricular (AVPV) nucleus, an area implicated in positive feedback. Our working model is that kisspeptin changes ionic conductances in GnRH neurons to increase their responsiveness to synaptic inputs. We hypothesized kisspeptin increases GnRH neuron excitability independent of time of day or estradiol. To test this, we studied GFP-identified GnRH neuron response to extrinsic stimuli (2 pA current steps, 0-30 pA, 500 ms) before and during kisspeptin treatment in acute 300µm brain slices from OVX+E and OVX mice in the AM and PM. Ionotropic GABAA and glutamate receptors were blocked to stop spike initiation by fast synaptic transmission. In all groups, kisspeptin decreased the minimum current needed to initiate spikes (p<0.05); once firing was initiated, kisspeptin increased the number of spikes fired at each current step. Over the course of a 20-minute whole-cell recording, action potential characteristics can shift; for example without treatment, action potential threshold depolarizes and cells can become less likely to fire. Kisspeptin reverses these effects (p<0.05). Kisspeptin also increased the afterdepolarization potential (ADP, p<0.05), measured at 100 ms after termination of the current step in traces with four action potentials. In some cells, additional action potentials were initiated during the ADP, but this occurred only during kisspeptin treatment (4/9 cells OVX AM, 2/11 OVX PM, 2/9 OVX+E AM, 4/7 OVX+E PM). Both action potential threshold and the ADP of GnRH neurons are determined by voltage-dependent sodium channels, suggesting kisspeptin may modulate sodium conductances. Kisspeptin-mediated effects on ADP and firing threshold were independent of time-of-day and estradiol treatment. Collectively, these data suggest changes in kisspeptin release during positive feedback rather than changes in response of the GnRH neuron to this neuromodulator help drive the increase in GnRH neuron excitability observed at this time.
Nothing to Disclose: CEA, SS, SMM