Physiologic Regulation of a Tetrodotoxin-Sensitive Sodium Influx That Mediates a Slow Afterdepolarization Potential in Gonadotropin-Releasing Hormone Neurons: Possible Implications for the Central Regulation of Fertility

Abstract

The brain controls fertility through release of gonadotropin-releasing hormone (GnRH), but the mechanisms underlying action potential patterning and GnRH release are not understood. We investigated whether GnRH neurons exhibit afterdepolarizing potentials (ADPs) and whether these are modified by reproductive state. Whole-cell current-clamp recordings of GnRH neurons in brain slices from ovariectomized mice revealed a slow ADP (sADP) after action potentials generated by brief current injection. Generating two or four spikes enhanced sADP amplitude and duration. sADP amplitude was not affected by blocking selected neurotransmitter/neuromodulator receptors, delayed-rectifier potassium channels, calcium-dependent cation channels, or hyperpolarization-activated cation channels but was halved by the calcium channel blocker cadmium and abolished by tetrodotoxin. Cadmium also reduced peak latency. Intrinsic mechanisms underlying the sADP were investigated using voltage-clamp protocols simulating action potential waveforms. A single action potential produced an inward current, which increased after double and quadruple stimulation. Cadmium did not affect current amplitude but reduced peak latency. Pretreatment with blockers of calcium-activated potassium currents (I KCa ) reproduced this shift and blocked subsequent cadmium-induced changes, suggesting cadmium changes latency indirectly by blocking I KCa . Tetrodotoxin abolished the inward current, suggesting that it is carried by sodium. In contrast, I KCa blockers increased the inward current, indicating that I KCa may oppose generation of the sADP. Strong sADPs were suprathreshold, generating repetitive spontaneous firing. I ADP , sADP, and excitability were enhanced by in vivo estradiol, which triggers a preovulatory surge of GnRH release. Physiological feedback modification of this inward current and resulting sADP may modulate action potential firing and subsequent GnRH release.

A simple integrative electrophysiological model of bursting GnRH neurons

“…Furthermore, in (Chu & Moenter, 2006) it has been shown, that the broadspectrum calcium channel blocker cadmium reduced the amplitude of DAP by 60%, although it has not reduced the amplitude of the corresponding current I DAP . The authors raise the possibility that this influence of DAP amplitude is caused through the modulation of calcium activated potassium currents.…”

“…It has been shown (Chu & Moenter, 2006) that DAPs, which contribute to bursting (Kuehl-Kovarik et al, 2005), observed in the case of GnRH neurons are TTX dependent. Furthermore, in (Chu & Moenter, 2006) it has been shown, that the broadspectrum calcium channel blocker cadmium reduced the amplitude of DAP by 60%, although it has not reduced the amplitude of the corresponding current I DAP .…”

“…This mechanism is the assumed Ca 2+ dependent regulation of sodium channels which, as we will show later, makes the model able to explain depolarizing afterpotentials (DAPs or afterdepolarizations ADPs). DAPs are considered an important characteristic feature of the electrophysiological behavior of GnRH neurons (Chu & Moenter, 2006), which contribute to bursting behavior (Kuehl-Kovarik et al, 2005). The simplification of the model framework takes place via the application of the 'simple model' described in (Izhikevich, 2005).…”

“…The model should be able to approximately reproduce the shape of action potentials (APs), and excitability properties observed in GnRH neurons originating from hypothalamic slices Chu & Moenter, 2006;Csercsik et al, 2010). Furthermore, the model should be able to reproduce dendritic AP generation (Roberts, Campbell, et al, 2008).…”

“…2. The model should be able to describe DAPs (KuehlKovarik et al, 2005;Chu & Moenter, 2006), because we suppose that DAPs significantly contribute to bursting behavior (Kuehl-Kovarik et al, 2005). 3.…”