title: Histamine facilitates GABAergic transmission in the rat entorhinal cortex: Roles of H1and H2receptors, Na+-permeable cation channels, and inward rectifier K+channels.
abstract: In the brain, histamine (HA) serves as a neuromodulator and a neurotransmitter released from the tuberomammillary nucleus (TMN). HA is involved in wakefulness, thermoregulation, energy homeostasis, nociception, and learning and memory. The medial entorhinal cortex (MEC) receives inputs from the TMN and expresses HA receptors (H1, H2, and H3). We investigated the effects of HA on GABAergic transmission in the MEC and found that HA significantly increased the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) with an EC50of 1.3 µM, but failed to significantly alter sIPSC amplitude. HA-induced increases in sIPSC frequency were sensitive to tetrodotoxin (TTX), required extracellular Ca2+, and persisted when GDP-β-S, a G-protein inactivator, was applied postsynaptically via the recording pipettes, indicating that HA increased GABA release by facilitating the excitability of GABAergic interneurons in the MEC. Recordings from local MEC interneurons revealed that HA significantly increased their excitability as determined by membrane depolarization, generation of an inward current at -65 mV, and augmentation of action potential firing frequency. Both H1and H2receptors were involved in HA-induced increases in sIPSCs and interneuron excitability. Immunohistochemical staining showed that both H1and H2receptors are expressed on GABAergic interneurons in the MEC. HA-induced depolarization of interneurons involved a mixed ionic mechanism including activation of a Na+-permeable cation channel and inhibition of a cesium-sensitive inward rectifier K+channel, although HA also inhibited the delayed rectifier K+channels. Our results may provide a cellular mechanism, at least partially, to explain the roles of HA in the brain. © 2017 Wiley Periodicals, Inc.
authors.affiliation: Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota.
authors.forename: Nicholas I
authors.identifier: 0000-0002-9012-6517
authors.initials: NI
authors.lastname: Cilz
authors.affiliation: Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota.
authors.forename: Saobo
authors.initials: S
authors.lastname: Lei
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002412:Cations / Q000378:metabolism; D002586:Cesium / Q000378:metabolism; D018728:Entorhinal Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006632:Histamine / Q000378:metabolism*; D017442:Histamine Agonists / Q000494:pharmacology; D006633:Histamine Antagonists / Q000494:pharmacology; D007395:Interneurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism; D011969:Receptors, Histamine H1 / Q000378:metabolism; D011970:Receptors, Histamine H2 / Q000378:metabolism; D018100:Receptors, Histamine H3 / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D046509:Tissue Culture Techniques; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D002412:Cations; D017442:Histamine Agonists; D006633:Histamine Antagonists; D024661:Potassium Channels, Inwardly Rectifying; D011963:Receptors, GABA-A; D011969:Receptors, Histamine H1; D011970:Receptors, Histamine H2; D018100:Receptors, Histamine H3; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D002586:Cesium; D005680:gamma-Aminobutyric Acid; D006632:Histamine; D002118:Calcium
keywords: GABA; entorhinal; histamine; neuromodulation; synaptic transmission