title: Histamine induces KCNQ channel-dependent gamma oscillations in rat hippocampus via activation of the H1 receptor.
abstract: Histamine is an aminergic neurotransmitter, which regulates wakefulness, arousal and attention in the central nervous system. Histamine receptors have been the target of efforts to develop pro-cognitive drugs to treat disorders such as Alzheimer's disease and schizophrenia. Cognitive functions including attention are closely associated with gamma oscillations, a rhythmical electrical activity pattern in the 30-80 Hz range, which depends on the synchronized activity of excitatory pyramidal cells and inhibitory fast-spiking interneurons. We set out to explore whether histamine has a role in promoting gamma oscillations in the hippocampus. Using in-situ hybridization we demonstrate that histamine receptor subtypes 1, 2 and 3 are expressed in stratum pyramidale of area CA3 in rats. We show that both pyramidal cells and fast-spiking interneurons depolarize and increase action potential firing in response to histamine in vitro. The activation of histamine receptors generates dose-dependent, transient gamma oscillations in area CA3 of the hippocampus - the locus of the gamma rhythm generator. We also demonstrate that this histamine effect is independent of muscarinic receptors. Using specific antagonists we provide evidence that histamine gamma rhythmogenesis specifically depends on the H1 receptor. Histamine also depolarized both pyramidal cells and fast-spiking interneurons and increased membrane resistance in pyramidal cells. The increased membrane resistance is potentially mediated by the inhibition of potassium channels because application of the KCNQ channel opener ICA110381 abolished the oscillations. Taken together our data demonstrate a novel and physiological mechanism for generating gamma oscillations in hippocampus and suggest a role for KCNQ channels in this cognition-relevant brain activity.
authors.affiliation: Neuronal Oscillations Laboratory, Neurogeriatrics Division, Center for Alzheimer Research, Dept. of Neurobiology, Care Sciences and Society, Karolinska Institutet, 14186 Stockholm, Sweden.
authors.forename: Richard
authors.initials: R
authors.lastname: Andersson
authors.affiliation: Dept. of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Galter
authors.affiliation: Neuronal Oscillations Laboratory, Neurogeriatrics Division, Center for Alzheimer Research, Dept. of Neurobiology, Care Sciences and Society, Karolinska Institutet, 14186 Stockholm, Sweden.
authors.forename: Daniela
authors.initials: D
authors.lastname: Papadia
authors.affiliation: Neuronal Oscillations Laboratory, Neurogeriatrics Division, Center for Alzheimer Research, Dept. of Neurobiology, Care Sciences and Society, Karolinska Institutet, 14186 Stockholm, Sweden. Electronic address: andre.fisahn@ki.se.
authors.forename: André
authors.initials: A
authors.lastname: Fisahn
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000831:Animals, Newborn; D001549:Benzamides / Q000494:pharmacology; D065818:Gamma Rhythm / Q000187:drug effects*; D005968:Glutamate Decarboxylase / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D006632:Histamine / Q000494:pharmacology*; D018494:Histamine Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D051656:KCNQ Potassium Channels / Q000378:metabolism*; D008297:Male; D049990:Membrane Transport Modulators / Q000494:pharmacology; D009415:Nerve Net / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects; D018377:Neurotransmitter Agents / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011968:Receptors, Histamine / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000378:metabolism
chemical_list: C582778:4-chloro-N-(6-chloropyridin-3-yl)benzamide; D001549:Benzamides; D018494:Histamine Agents; D051656:KCNQ Potassium Channels; D049990:Membrane Transport Modulators; D018377:Neurotransmitter Agents; D011725:Pyridines; D011968:Receptors, Histamine; D006632:Histamine; D043222:Ubiquitin Thiolesterase; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1
keywords: Cognition; Gamma oscillation; Hippocampus; Histamine H1 receptor; KCNQ channel; Schizophrenia