Abstract
Histamine is an important neurotransmitter that contributes to various processes, including the sleep-wake cycle, learning, memory, and stress responses. Its actions are mediated through histamine H1–H4 receptors. Gene knockout and pharmacological studies have revealed the importance of H1 receptors in learning and memory, regulation of aggression, and wakefulness. H1 receptors are abundantly expressed on neurons and astrocytes. However, to date, studies selectively investigating the roles of neuronal and astrocytic H1 receptors in behaviour are lacking. We generated novel astrocyte- and neuron-specific conditional knockout (cKO) mice to address this gap in knowledge. cKO mice showed cell-specific reduction of H1 receptor gene expression. Behavioural assessment revealed significant changes and highlighted the importance of H1 receptors on both astrocytes and neurons. H1 receptors on both cell types played a significant role in anxiety. Astrocytic H1 receptors were involved in regulating aggressive behaviour, circadian rhythms, and quality of wakefulness, but not sleep behaviour. Our results emphasise the roles of neuronal H1 receptors in recognition memory. In conclusion, this study highlights the novel roles of H1 receptors on astrocytes and neurons in various brain functions.
Highlights
Histamine is an important neurotransmitter that contributes to various processes, including the sleepwake cycle, learning, memory, and stress responses
Novel astrocyte-specific glial fibrillary acidic protein- (GFAP) Cre Hrh1f/f and neuron-specific Ca2+/calmodulin-dependent protein kinase II- (CaMKII) Cre Hrh1f/f mice were successfully generated by crossing GFAP-Cre-29 or CaMKII-Cre-transgene[30] positive mice with Hrh1f/f mice that carried conditional Hrh[1] alleles; two loxP sites flanked the coding sequence of Hrh[1] in exon 3 (Fig. 1A)
Histamine H1 receptors in the central nervous system (CNS) are involved in various physiological processes
Summary
Histamine is an important neurotransmitter that contributes to various processes, including the sleepwake cycle, learning, memory, and stress responses. This study highlights the novel roles of H1 receptors on astrocytes and neurons in various brain functions. Recent studies reported a role of H1 receptor-mediated astrocyte signalling in the regulation of glutamate release and clearance by (upper) or GFAP-Cre (lower) transgenic mice (cropped agarose gels are shown, see Supplementary Fig. S1 for full length gels). Compelling evidence demonstrates the multifarious functions of astrocytic H1 receptors in vitro, emphasising the need to selectively assess the impact of neuronal and astrocytic H1 receptor signalling on behaviour. We developed novel conditional knockout (cKO) mice to selectively reduce Hrh[1] expression in either astrocytes or neurons. The aim of this study was to assess phenotypes of cKO mice and compare them to controls to better understand the impact of cell-specific H1 receptor signalling on brain function
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