It is an exciting time for translational

It is an exciting time for translational histamine research, since preclinical studies show potential value for histamine receptor ligands. As reviewed above, there are several concerns for future studies of histamine and its role in the CNS. 1) Because of the availability of HDC-Cre mice (Williams et al., 2014, Yanovsky et al., 2012), histaminergic neuron specific modulation can be achieved through the use of optogenetic or chemogenetic approaches. This has the potential to rapidly advance exploration of the role of histaminergic circuits in CNS disorders. Optogenetics uses light-responsive cellular elements, such as ChR2 or archaerhodopsin (Arch), to produce stimulation or inhibition of neurons. One major advantage of this tool is the ability to generate rapid kinetic models, leading to more precise temporal and geographic targeting (Deisseroth, 2015). On the other hand, the chemogenetic approach is an alternative route towards targeted and temporal increase or suppression of neuronal excitability via designer receptors exclusively activated by designer drugs (Roth, 2016). A merit for this approach is that the modulation of neuron firing can persist for hours or even days. In addition, since other neurotransmitters, such as GABA or dopamine, may be co-released from histaminergic neurons (Yanovsky et al., 2011, Yu et al., 2015), we need to be concerned about the action of other neurotransmitters, when the activity of histaminergic neurons is manipulated. 2) The inconsistent actions of histamine receptors have been observed, which is likely due to the discrepant actions of histamine receptors in different cell types. The use of conditional knockout mice is an optimal approach to shed light on the cell type selective action of histamine receptors. In addition, most actions of histamine in the aspirin solubility synthesis are mediated by the H1R, but not the H2R, making the role of the H2R a bit mysterious. This is due to the fact that it is expressed in the same location and in comparable amounts as the H1R. Investigation of the action of the H2R in specific cell types in the brain may provide new targets for the treatment of CNS disorders. Recently, we found that the H2R in oligodendrocytes regulates differentiation to improve remyelination and cognitive abilities in postnatal mice exposed to hypoxia/ischemia (unpublished data). 3) Several diverse histamine receptor isoforms are present in the CNS, and the ligands may show different activities for different isoforms. For example, (R) sopromidine is an antagonist at the short isoform of H3R, but a full agonist at the long isoform of H3R (Gbahou et al., 2012). Therefore, it is important to identify both the isoform and the function of the histamine receptors present in a particular cell type. Based on the aforementioned studies, development of drugs that selectively target certain receptors in specific cell-types might provide precise therapeutic approaches with enhanced efficacy and/or decreased incidence of side effects. 4) The expression and role of the H4R need to be evaluated in more detail and under different pathologic settings, which may play a critical role in neuroinflammation and also serve as a therapeutic target. More rigorous experiments should be undertaken for such studies; this is especially important since H3R ligands may also act on H4R, and H4R ligands may display different pharmacological properties in different species and under different experimental conditions (Panula et al., 2015). For example, JNJ-7777120 may display partial inverse agonistic activity on human H4R, whereas it displays partial agonistic activities on rat, mouse, and canine species specific H4R variants (Schnell et al., 2011). 5) Due to the high constitutive activity of H3R and H4R, receptor inverse agonists may also have histamine independent effects. The functional mechanisms that are modulated through direct binding of proteins to the receptors are found for the downstream pathway of histamine receptors, such as the binding of CLIC4 with the H3R for the induction of autophagy (Yan et al., 2014) and the direct binding dopamine D1R or D2R with the H3R for the modulation of MSN firing (Ferrada et al., 2008, Ferrada et al., 2009). Therefore, exploring the role of the proteins that directly bind the histamine receptors may help to understand the mechanism of the action of histamine receptors. 6) Mast cell-derived histamine is suggested to affect hypothalamic neurons, and is involved in endocrine control and homoeostatic regulation, but its relative limited distribution leads to less attention for it (Kawakami et al., 2000). Recently, cerebral mast cells have been suggested to participate in some CNS disorders, including cerebral ischemia, AD, traumatic brain injury, and multiple sclerosis (Conti and Kempuraj, 2016, Hendrix et al., 2013, Shaik-Dasthagirisaheb and Conti, 2016). Although selective depletion of histamine in mast cells is not available at this moment, using mast cell deficient W/Wv mice helps to elucidate the role of histamine in mast cells. Moreover, other possible nonneuronal sources of histamine, including that from microglia and microvascular endothelial cells (Katoh et al., 2001, Yamakami et al., 2000), may also have potential action in CNS disorders (Fig. 4).