Glycine released from astrocytes as well as neurons is

Glycine released from astrocytes as well as neurons is also known as a co-agonist of NMDAR (Roux and Supplisson, 2000). Neuronal glycine in mouse hippocampus might be released from glutamatergic terminals (Muller et al., 2013) that express functional nigericin receptors (Rodriguez et al., 1997). Glycine release from cortical astrocytes is regulated by astrocytic glycine transporter GlyT1 in a reversed mode via signaling coupled to dopamine D5 receptors (Shibasaki et al., 2017). The possible contribution of H1 receptor-mediated glycine release from astrocytes and neurons cannot be excluded in the present study. There has recently been a controversy over the source of D-serine for the regulation of synaptic plasticity. It is reported that D-serine may primarily derive from neurons, and astrocytes only affect the D-serine level by synthesizing L-serine that shuttles to neurons (Wolosker et al., 2016). Biosynthetic enzyme of D-serine, serine racemase (SR), is predominantly localized in pyramidal neurons rather than astrocytes in the hippocampus under normal conditions (Miya et al., 2008). Conditional knockout of neuronal serine racemase, but not astrocytic one, significantly suppressed moderation of LTP induced by 1 × 100 Hz protocol in the hippocampal CA1 (Benneyworth et al., 2012). On the other hand, Papouin et al. (2017a) advocated that the hypothesis supportive of neuronal D-serine could have resulted from erroneous interpretations of experimental data: e.g., (1) the suggested abundance of SR and D-serine in neurons came from the ambiguity of immunostaining at neuropil regions that could not allow to conclude their cellular abundance or cellular origin of D-serine; (2) any conclusive evidence has not been provided for the mechanism underlying the release of neuronal D-serine; and (3) test for conditional knockout of neuronal SR was performed without knocking out the sufficient level of neuronal SR. Therefore, the definite conclusion has yet to be attained for the neuronal and astrocytic D-serine hypotheses. Although we used a glial toxin FAC to determine possible involvement of astrocytes in the present study, it would be possible that FAC may exhaust neuronal D-serine through suppression of L-serine supply by astrocytes. The regulation of neuronal D-serine release by neuronal H1 receptors may also be involved in the NMDAR-mediated EPSCs and LTP (Fig. 7). In conclusion, we have demonstrated that the histamine H1 receptor antagonist/inverse agonists, pyrilamine and cetirizine, can attenuates both NMDAR-mediated EPSCs recorded in CA1 pyramidal neurons and LTP induced at Shaffer colateral-CA1 pyramidal neuron synapses. The proposed mechanism that underlies the pyrilamine- and cetirizine-induced attenuation of hippocampal synaptic responses is as follows: under basal conditions, H1 receptors in the hippocampus could be persistently activated by their constitutive activity or endogenous histamine released from histaminergic nerve terminals, leading to the release of D-serine from astrocytes and/or neurons and enhancement of NMDAR-mediated EPSCs and LTP. An H1 receptor antagonist/inverse agonist could inhibit the H1 receptor-mediated modulation of D-serine release and thereby attenuate NMDAR-mediated synaptic excitation and plasticity (Fig. 7).
Conflict of interest statement
Acknowledgments This work was partially supported by JSPS KAKENHI grants (Numbers 18200026, 20021027, 16K19023), a grant from the Smoking Research Fundation of Japan and a grant from the Nakatomi Foundation, Japan. We also thank Ms. Keiko Tokumaru for her technical and secretarial assistance.
Introduction Histamine is implicated in a variety of physiological and pathophysiological functions, including inflammatory processes (Mahdy and Webster, 2014). Four histamine receptors subtypes (histamine H1-H4 receptors) have been identified so far. All of them belong to the seven-transmembrane domain receptors, and are characterized with a different structure, function, distribution and affinity towards histamine (Leurs et al., 2009, Zampeli and Tiligada, 2009). The H1 receptor is involved in: cellular migration, vasodilation, bronchoconstriction and nociception (Bakker et al., 2001), whereas the H2 receptor modifies gastric acid secretion, vascular permeability and airway mucus production (Seifert et al., 2013). The H3 receptor is playing important role in neurotransmission (Singh and Jadhav, 2013). Finally H4 receptor is reported to be involved in inflammation (Tiligada, 2012). Histamine has been shown to activate immune cells, such as eosinophils, mast cells and dendritic cells. It is known that human eosinophils exhibit functional expression of three histamine receptors (H1, H2, H4) (Ezeamuzie and Philips, 2000, Ling et al., 2004, Pincus et al., 1982, Reher et al., 2012). Nevertheless, the functional importance of each three histamine receptors, on human eosinophils has not been yet comprehensively characterized. This is mainly due to technical challenges in obtaining highly purified human eosinophils with preserved viability and functionality. Still using various methods of eosinophils isolation, it was demonstrated that activation of histamine H4 receptors on human eosinophils results in intracellular calcium concentration flux, cytoskeleton and cellular shape change, adhesion molecules upregulation, cellular migration and chemotaxis (Buckland et al., 2003, Ling et al., 2004, Reher et al., 2012).