Histamine H(1) receptor on astrocytes and neurons controls distinct aspects of mouse behaviour

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 H(1)–H(4) receptors. Gene knockout and pharmacological studies have revealed the importance of H(1) receptors in learning and memory, regulation of aggression, and wakefulness. H(1) receptors are abundantly expressed on neurons and astrocytes. However, to date, studies selectively investigating the roles of neuronal and astrocytic H(1) 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 H(1) receptor gene expression. Behavioural assessment revealed significant changes and highlighted the importance of H(1) receptors on both astrocytes and neurons. H(1) receptors on both cell types played a significant role in anxiety. Astrocytic H(1) receptors were involved in regulating aggressive behaviour, circadian rhythms, and quality of wakefulness, but not sleep behaviour. Our results emphasise the roles of neuronal H(1) receptors in recognition memory. In conclusion, this study highlights the novel roles of H(1) receptors on astrocytes and neurons in various brain functions.