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Estradiol Enhances the Depolarizing Response to GABA and AMPA Synaptic Conductances in Arcuate Kisspeptin Neurons by Diminishing Voltage-Gated Potassium Currents.
J Neurosci 2019; 39(48):9532-9545JN

Abstract

Synaptic and intrinsic properties interact to sculpt neuronal output. Kisspeptin neurons in the hypothalamic arcuate nucleus help convey homeostatic estradiol feedback to central systems controlling fertility. Estradiol increases membrane depolarization induced by GABAA receptor activation in these neurons. We hypothesized that the mechanisms underlying estradiol-induced alterations in postsynaptic response to GABA, and also AMPA, receptor activation include regulation of voltage-gated potassium currents. Whole-cell recordings of arcuate kisspeptin neurons in brain slices from ovariectomized (OVX) and OVX+estradiol (OVX+E) female mice during estradiol negative feedback revealed that estradiol reduced capacitance, reduced transient and sustained potassium currents, and altered voltage dependence and kinetics of transient currents. Consistent with these observations, estradiol reduced rheobase and action potential latency. To study more directly interactions between synaptic and active intrinsic estradiol feedback targets, dynamic clamp was used to simulate GABA and AMPA conductances. Both GABA and AMPA dynamic clamp-induced postsynaptic potentials (PSPs) were smaller in neurons from OVX than OVX+E mice; blocking transient potassium currents eliminated this difference. To interrogate the role of the estradiol-induced changes in passive intrinsic properties, different Markov model structures based on the properties of the transient potassium current in cells from OVX or OVX+E mice were combined in silico with passive properties reflecting these two endocrine conditions. Some of tested models reproduced the effect on PSPs in silico, revealing that AMPA PSPs were more sensitive to changes in capacitance. These observations support the hypothesis that PSPs in arcuate kisspeptin neurons are regulated by estradiol-sensitive mechanisms including potassium conductances and membrane properties.SIGNIFICANCE STATEMENT Kisspeptin neurons relay estradiol feedback to gonadotropin-releasing hormone neurons, which regulate the reproductive system. The fast synaptic neurotransmitters GABA and glutamate rapidly depolarize arcuate kisspeptin neurons and estradiol increases this depolarization. Estradiol reduced both potassium current in the membrane potential range typically achieved during response to fast synaptic inputs and membrane capacitance. Using simulated GABA and glutamate synaptic inputs, we showed changes in both the passive and active intrinsic properties induced by in vivo estradiol treatment affect the response to synaptic inputs, with capacitance having a greater effect on response to glutamate. The suppression of both passive and active intrinsic properties by estradiol feedback thus renders arcuate kisspeptin neurons more sensitive to fast synaptic inputs.

Authors+Show Affiliations

Departments of Molecular and Integrative Physiology.Department of Biological Sciences, University of Missouri, Columbia, Missouri 65211.Departments of Molecular and Integrative Physiology.Department of Biological Sciences, University of Missouri, Columbia, Missouri 65211.Departments of Molecular and Integrative Physiology, smoenter@umich.edu. Obstetrics and Gynecology. Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109-5622, and.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31628184

Citation

DeFazio, R Anthony, et al. "Estradiol Enhances the Depolarizing Response to GABA and AMPA Synaptic Conductances in Arcuate Kisspeptin Neurons By Diminishing Voltage-Gated Potassium Currents." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 39, no. 48, 2019, pp. 9532-9545.
DeFazio RA, Navarro MA, Adams CE, et al. Estradiol Enhances the Depolarizing Response to GABA and AMPA Synaptic Conductances in Arcuate Kisspeptin Neurons by Diminishing Voltage-Gated Potassium Currents. J Neurosci. 2019;39(48):9532-9545.
DeFazio, R. A., Navarro, M. A., Adams, C. E., Milescu, L. S., & Moenter, S. M. (2019). Estradiol Enhances the Depolarizing Response to GABA and AMPA Synaptic Conductances in Arcuate Kisspeptin Neurons by Diminishing Voltage-Gated Potassium Currents. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 39(48), pp. 9532-9545. doi:10.1523/JNEUROSCI.0378-19.2019.
DeFazio RA, et al. Estradiol Enhances the Depolarizing Response to GABA and AMPA Synaptic Conductances in Arcuate Kisspeptin Neurons By Diminishing Voltage-Gated Potassium Currents. J Neurosci. 2019 Nov 27;39(48):9532-9545. PubMed PMID: 31628184.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Estradiol Enhances the Depolarizing Response to GABA and AMPA Synaptic Conductances in Arcuate Kisspeptin Neurons by Diminishing Voltage-Gated Potassium Currents. AU - DeFazio,R Anthony, AU - Navarro,Marco A, AU - Adams,Caroline E, AU - Milescu,Lorin S, AU - Moenter,Suzanne M, Y1 - 2019/10/18/ PY - 2019/02/15/received PY - 2019/09/24/revised PY - 2019/10/07/accepted PY - 2020/05/27/pmc-release PY - 2019/10/20/pubmed PY - 2019/10/20/medline PY - 2019/10/20/entrez KW - AMPA KW - GABA KW - dynamic clamp KW - estradiol KW - postsynaptic potential KW - potassium currents SP - 9532 EP - 9545 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J. Neurosci. VL - 39 IS - 48 N2 - Synaptic and intrinsic properties interact to sculpt neuronal output. Kisspeptin neurons in the hypothalamic arcuate nucleus help convey homeostatic estradiol feedback to central systems controlling fertility. Estradiol increases membrane depolarization induced by GABAA receptor activation in these neurons. We hypothesized that the mechanisms underlying estradiol-induced alterations in postsynaptic response to GABA, and also AMPA, receptor activation include regulation of voltage-gated potassium currents. Whole-cell recordings of arcuate kisspeptin neurons in brain slices from ovariectomized (OVX) and OVX+estradiol (OVX+E) female mice during estradiol negative feedback revealed that estradiol reduced capacitance, reduced transient and sustained potassium currents, and altered voltage dependence and kinetics of transient currents. Consistent with these observations, estradiol reduced rheobase and action potential latency. To study more directly interactions between synaptic and active intrinsic estradiol feedback targets, dynamic clamp was used to simulate GABA and AMPA conductances. Both GABA and AMPA dynamic clamp-induced postsynaptic potentials (PSPs) were smaller in neurons from OVX than OVX+E mice; blocking transient potassium currents eliminated this difference. To interrogate the role of the estradiol-induced changes in passive intrinsic properties, different Markov model structures based on the properties of the transient potassium current in cells from OVX or OVX+E mice were combined in silico with passive properties reflecting these two endocrine conditions. Some of tested models reproduced the effect on PSPs in silico, revealing that AMPA PSPs were more sensitive to changes in capacitance. These observations support the hypothesis that PSPs in arcuate kisspeptin neurons are regulated by estradiol-sensitive mechanisms including potassium conductances and membrane properties.SIGNIFICANCE STATEMENT Kisspeptin neurons relay estradiol feedback to gonadotropin-releasing hormone neurons, which regulate the reproductive system. The fast synaptic neurotransmitters GABA and glutamate rapidly depolarize arcuate kisspeptin neurons and estradiol increases this depolarization. Estradiol reduced both potassium current in the membrane potential range typically achieved during response to fast synaptic inputs and membrane capacitance. Using simulated GABA and glutamate synaptic inputs, we showed changes in both the passive and active intrinsic properties induced by in vivo estradiol treatment affect the response to synaptic inputs, with capacitance having a greater effect on response to glutamate. The suppression of both passive and active intrinsic properties by estradiol feedback thus renders arcuate kisspeptin neurons more sensitive to fast synaptic inputs. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/31628184/Estradiol_enhances_the_depolarizing_response_to_GABA_and_AMPA_synaptic_conductances_in_arcuate_kisspeptin_neurons_by_diminishing_voltage-gated_potassium_currents L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=31628184 DB - PRIME DP - Unbound Medicine ER -