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The Journal of Neuroscience, November 15, 2006, 26(46):11961-11973; doi:10.1523/JNEUROSCI.3171-06.2006

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Behavioral/Systems/Cognitive
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

Zhiguo Chu¹ and Suzanne M. Moenter^1,2

Departments of ¹Medicine and ²Cell Biology, University of Virginia, Charlottesville, Virginia 22908

Correspondence should be addressed to Suzanne M. Moenter, Departments of Medicine and Cell Biology, University of Virginia, Charlottesville, Virginia 22908. Email: moenter{at}virginia.edu

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.

Key words: GnRH; intrinsic activity; sodium current; excitability; neuroendocrine; afterdepolarizing potential; feedback regulation

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Received July 25, 2006; revised Oct. 11, 2006; accepted Oct. 11, 2006.

Correspondence should be addressed to Suzanne M. Moenter, Departments of Medicine and Cell Biology, University of Virginia, Charlottesville, Virginia 22908. Email: moenter{at}virginia.edu

This article has been cited by other articles:

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