Histamine H₁ 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 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.