Molecular mechanisms that drive estradiol-dependent burst firing of Kiss1 neurons in the rostral periventricular preoptic area

Am J Physiol Endocrinol Metab. 2013 Dec 1;305(11):E1384-97. doi: 10.1152/ajpendo.00406.2013. Epub 2013 Oct 8.


Kisspeptin (Kiss1) neurons in the rostral periventricular area of the third ventricle (RP3V) provide excitatory drive to gonadotropin-releasing hormone (GnRH) neurons to control fertility. Using whole cell patch clamp recording and single-cell (sc)RT-PCR techniques targeting Kiss1-CreGFP or tyrosine hydroxylase (TH)-EGFP neurons, we characterized the biophysical properties of these neurons and identified the critical intrinsic properties required for burst firing in 17β-estradiol (E2)-treated, ovariectomized female mice. One-fourth of the RP3V Kiss1 neurons exhibited spontaneous burst firing. RP3V Kiss1 neurons expressed a hyperpolarization-activated h-current (Ih) and a T-type calcium current (IT), which supported hyperpolarization-induced rebound burst firing. Under voltage clamp conditions, all Kiss1 neurons expressed a kinetically fast Ih that was augmented 3.4-fold by high (LH surge-producing)-E2 treatment. scPCR analysis of Kiss1 neurons revealed abundant expression of the HCN1 channel transcripts. Kiss1 neurons also expressed a Ni(2+)- and TTA-P2-sensitive IT that was augmented sixfold with high-E2 treatment. CaV3.1 mRNA was also highly expressed in these cells. Current clamp analysis revealed that rebound burst firing was induced in RP3V Kiss1 neurons in high-E2-treated animals, and the majority of Kiss1 neurons had a hyperpolarization threshold of -84.7 mV, which corresponded to the V½ for IT de-inactivation. Finally, Kiss1 neurons in the RP3V were hyperpolarized by μ- and κ-opioid and GABAB receptor agonists, suggesting that these pathways also contribute to rebound burst firing. Therefore, Kiss1 neurons in the RP3V express the critical channels and receptors that permit E2-dependent rebound burst firing and provide the biophysical substrate that drives the preovulatory surge of GnRH.

Keywords: RP3V; T-type calcium channel; burst firing; kisspeptin; pacemaker current.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Estradiol / pharmacology*
  • Female
  • Follicular Phase / drug effects
  • Follicular Phase / metabolism
  • Gonadotropin-Releasing Hormone / metabolism
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Kisspeptins / genetics
  • Kisspeptins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neurons / drug effects
  • Neurons / physiology*
  • Ovariectomy
  • Preoptic Area / drug effects
  • Preoptic Area / metabolism*
  • Signal Transduction / drug effects
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / genetics
  • Third Ventricle / drug effects
  • Third Ventricle / metabolism


  • Kiss1 protein, mouse
  • Kisspeptins
  • Green Fluorescent Proteins
  • Gonadotropin-Releasing Hormone
  • Estradiol