title: Enhanced histaminergic neurotransmission and sleep-wake alterations, a study in histamine H3-receptor knock-out mice.
abstract: Long-term abolition of a brain arousal system impairs wakefulness (W), but little is known about the consequences of long-term enhancement. The brain histaminergic arousal system is under the negative control of H3-autoreceptors whose deletion results in permanent enhancement of histamine (HA) turnover. In order to determine the consequences of enhancement of the histaminergic system, we compared the cortical EEG and sleep-wake states of H3-receptor knockout (H3R-/-) and wild-type mouse littermates. We found that H3R-/-mice had rich phenotypes. On the one hand, they showed clear signs of enhanced HA neurotransmission and vigilance, i.e., a higher EEG θ power during spontaneous W and a greater extent of W or sleep restriction during behavioral tasks, including environmental change, locomotion, and motivation tests. On the other hand, during the baseline dark period, they displayed deficient W and signs of sleep deterioration, such as pronounced sleep fragmentation and reduced cortical slow activity during slow wave sleep (SWS), most likely due to a desensitization of postsynaptic histaminergic receptors as a result of constant HA release. Ciproxifan (H3-receptor inverse agonist) enhanced W in wild-type mice, but not in H3R-/-mice, indicating a functional deletion of H3-receptors, whereas triprolidine (postsynaptic H1-receptor antagonist) or α-fluoromethylhistidine (HA-synthesis inhibitor) caused a greater SWS increase in H3R-/- than in wild-type mice, consistent with enhanced HA neurotransmission. These sleep-wake characteristics and the obesity phenotypes previously reported in this animal model suggest that chronic enhancement of histaminergic neurotransmission eventually compromises the arousal system, leading to sleep-wake, behavioral, and metabolic disorders similar to those caused by voluntary sleep restriction in humans.
authors.affiliation: Integrative Physiology of the Brain Arousal Systems, Lyon Neuroscience Research Center, INSERM U1028-CNRS UMR 5292, Faculty of Medicine, Claude Bernard University, Lyon, France.
authors.forename: Elise
authors.initials: E
authors.lastname: Gondard
authors.forename: Christelle
authors.initials: C
authors.lastname: Anaclet
authors.forename: Hidéo
authors.initials: H
authors.lastname: Akaoka
authors.forename: Rui-Xian
authors.initials: RX
authors.lastname: Guo
authors.forename: Mei
authors.initials: M
authors.lastname: Zhang
authors.forename: Colette
authors.initials: C
authors.lastname: Buda
authors.forename: Patricia
authors.initials: P
authors.lastname: Franco
authors.forename: Hidehito
authors.initials: H
authors.lastname: Kotani
authors.forename: Jian-Sheng
authors.initials: JS
authors.lastname: Lin
mesh_terms: D000818:Animals; D005260:Female; D006632:Histamine / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018100:Receptors, Histamine H3 / Q000172:deficiency*; D012890:Sleep / Q000235:genetics / Q000502:physiology; D012894:Sleep Stages / Q000235:genetics / Q000502:physiology*; D009435:Synaptic Transmission / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation / Q000235:genetics; D014851:Wakefulness / Q000235:genetics / Q000502:physiology*
chemical_list: D018100:Receptors, Histamine H3; D006632:Histamine