In the CNS histamine is known to regulate

In the CNS, Gabapentin is known to regulate sleep and wakefulness, learning and memory, feeding, and energy. Here, we address its actions in relation to CNS disorders, and emphasize potential clinical applications of histamine receptor ligands (Table 1). In addition, as the effect of histamine on neuroprotection is often ignored, we spend considerable space to review those actions that are predominantly under the context of cerebral ischemia, which broadens the clinical applications of histamine related ligands.
Prospect for the study of histamine in the CNS
Conclusion
Conflict of interest statement
Acknowledgments This work was supported by the National Natural Science Foundation of China (81221003, 81273506, 81473186, 81673405). We are very grateful to Dr. John Hugh Snyder for language editing and Ying Wang for polishing schematic diagrams.
Introduction Tics are seen at least transiently in up to 20% of children, and a smaller fraction of adults. Tourette syndrome (TS), which consists of persistent vocal and motor tics, has a prevalence of ∼0.7% (Scahill and Dalsgaard, 2013). Tics are commonly comorbid with other neuropsychiatric pathology, including obsessive–compulsive disorder (OCD), attentional difficulties, and autism (Martino and Leckman, 2013). Their etiology, however, remains poorly understood. Recently, dysregulation of histamine (HA) has been associated with TS, tic disorders, and related pathology (Pittenger, 2017). A rare mutation in the histidine decarboxylase (Hdc) gene, which is required for HA biosynthesis, was identified as a high-penetrance genetic cause of TS (Ercan-Sencicek et al., 2010, Castellan Baldan et al., 2014). Hdc knockout (KO) mice constitute a model of this pathophysiology (Pittenger, 2017). Hdc KO mice exhibit repetitive behavioral pathology (Castellan Baldan et al., 2014), including elevated grooming after acute stress (Xu et al., 2015). While such repetitive behaviors are not identical to tics, they suggest recapitulation of relevant pathological changes in the model. Other genetic studies have suggested that abnormalities in HA modulatory neurotransmission may contribute to tic disorders beyond the single pedigree in which the original Hdc mutation was identified (Fernandez et al., 2012, Karagiannidis et al., 2013). Histamine acts on four G-protein-coupled receptors, H1R-H4R. The H3R receptor is expressed at high levels in the central nervous system (Haas et al., 2008, Panula and Nuutinen, 2013). It has high constitutive activity and can thus modulate intracellular signaling even in the absence of agonist (Morisset et al., 2000). H3R has classically been considered to be coupled to Gαi and to act presynaptically to reduce neurotransmitter release – both of HA itself and of other transmitters, including DA and glutamate (Schlicker et al., 1994, Haas et al., 2008, Ellender et al., 2011). More recently it has been found that much of the H3R in the striatum is post-synaptic, and that it couples to intracellular signaling cascades in striatal medium spiny neurons (MSNs) in complex and cell type-specific ways (Ferrada et al., 2008, Ferrada et al., 2009, Moreno et al., 2011, Panula and Nuutinen, 2013, Moreno et al., 2014, Rapanelli et al., 2016). H3R can heterodimerize with dopamine D1 and D2 receptors ex vivo and can modulate mitogen-activated protein kinase (MAPK) signaling (Ferrada et al., 2008, Ferrada et al., 2009, Moreno et al., 2011). We have replicated this regulation of MAPK signaling in D1-expressing striatonigral MSNs (dMSNs) in vivo (Rapanelli et al., 2016). In D2-expressing striatopallidal MSNs (iMSNs), in contrast, H3R activation modulates signaling through the protein kinase B (Akt) pathway (Rapanelli et al., 2016). In a recent study, we demonstrated that H3R is elevated in the striatum in Hdc KO mice, and its activation in the striatum produces stereotypies in this model (Rapanelli et al., 2017). Here we characterize differential regulation of MAPK and Akt signaling in dMSNs and iMSNs by the H3R agonist R-aminomethylhistamine (RAMH) in Hdc KO mice.