2.5 H4R and neural excitability
The H4R is recently discovered in the last decades, which is mainly located in microglia in the central nervous system (CNS) (Connelly et al., 2009; Raible, Lenahan, Fayvilevich, Kosinski & Schulman, 1994). At present, it is controversial whether the expression of H4R is on neurons or not (Connelly et al., 2009; Schneider & Seifert, 2016). The human H4R gene is located on chromosome 18, similar to H3R, which is coupled to Gi/o-protein coupled receptor (Cogé, Guénin, Rique, Boutin & Galizzi, 2001). In the brain, H4R was distributed in the dorsal root ganglia, hippocampus, and cerebral cortex (Yuan & Silberstein, 2018). Similar to other histamine receptors, H4R increases calcium release (Li, Carozza, Shatos, Hodges & Dartt, 2012), which is crucial for regulating neuron synaptic excitability (Carrasco, Jaimovich, Kemmerling & Hidalgo, 2004).
Activation of H4R leads to inhibition of CREB in the cerebellar vermis and prefrontal cortex (Fernandes & Serafim, 2019). Also, H4R targets and inactivates the downstream extracellular signal-regulated kinase (ERK)-CREB pathway (Sanna, Mello, Masini & Galeotti, 2018). H4R antagonists inhibit vestibular neuron activity (Desmadryl et al., 2012), suggests H4R involves in vestibular neuron excitability. Agonists or antagonists target H4R are commonly used to assess the function of H4R in some behavioral and disease phenotypes (Fernandes & Serafim, 2019; Fernandes, Serafim, Gianlorenco & Mattioli, 2017; Sanna, Borgonetti, Masini & Galeotti, 2020; Zhou et al., 2019). Recently years, H4R KO mice were also applied to investigate the behavioral phenotype and its neural function (Sanna, Ghelardini, Thurmond, Masini & Galeotti, 2017).