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  • br Discussion Our results showed

    2021-11-19


    Discussion Our results showed that the histamine H1 receptor antagonist/inverse agonists, pyrilamine and cetirizine, attenuated not only NMDAR-mediated synaptic current but also LTP in Shaffer collateral-CA1 pyramidal neuron synapses. The H1 receptor antagonist/inverse agonist-induced attenuation was abolished by treatment with the glial metabolism inhibitor FAC or the gliotransmitter D-serine. Therefore, as illustrated in Fig. 7, we propose that persistent activation of hippocampal H1 receptors in response to the tonic release of endogenous histamine and/or a constitutive activity of H1 receptors can lead to facilitation of the NMDAR activity on CA1 pyramidal neurons as well as LTP in CA1 synapses, which could be attenuated by exogenous application of H1 receptor antagonist/inverse agonists. The mechanism underlying this H1 receptor-mediated enhancement of glutamatergic transmission at Shaffer collateral-CA1 pyramidal neuron synapses could be related to the astrocyte activity and liberation of D-serine as discussed below. NMDAR activity and LTP in the CA1 are closely associated with regulation of cognitive function, including learning and memory (Morris et al., 1986). Hence, hippocampal H1 receptors are involved in maintaining diverse cognitive functions and expressing the symptoms of cognitive disorders. Lines of evidence have provided support for the notion of hippocampal H1 receptor-mediated cognitive regulation. For example, H1 receptor knockout mice exhibit pronounced deficits in hippocampus-dependent spatial learning and memory (Ambrée et al., 2014). Moreover, previous studies have shown that systemic administration of various H1 receptor antagonist/inverse agonists impairs spatial memory performance and hippocampal theta activities in rats (Masuoka et al., 2007). This impairment was antagonized by hippocampal injection of H1 receptor agonists (Masuoka and Kamei, 2007). In humans, positron emission tomography using [11C] doxepine, a radio ligand for the H1 receptor, has shown that the binding potency of H1 receptors displayed a significant decrease in certain Fomepizole regions, particularly the frontal and temporal cortices, including the hippocampus, of patients with Alzheimer's disease when compared with elderly individuals without symptoms (Higuchi et al., 2000). A number of electrophysiological experiments have focused on the interaction between histamine receptors and NMDARs in the hippocampus. Histamine at an intermediate concentration (1–10 μM) was reported to persistently potentiate, via H1 and H2 receptor activation, spontaneous discharges in CA1 pyramidal neurons in rat hippocampal slices through involvement of NMDARs and adenylate cyclase/PKA-signaling cascades, whereas a low concentration (0.1 μM) of histamine transiently attenuated the firing via H1 receptor activation (Selbach et al., 1997). High concentration (100 μM) of histamine was shown to potentiate the NMDA component of autaptic transmission onto hippocampal pyramidal neuron in culture via a histamine receptor-independent mechanism (Bekkers, 1993). In hippocampal slices, high concentration (10–100 μM) of histamine slightly attenuated fEPSPs in the CA1, but elicited LTP of fEPSPs when combined with conditioning of weak tetanus stimuli through the mechanism dependent of NMDARs and independent of H1 and H2 receptors (Brown et al., 1995). It appears therefore that histamine at 0.l–10 μM might elicit the activation of H1 receptor in the hippocampus, whereas higher concentration of histamine may result in facilitation of the NMDAR activity in a histamine receptor-independent manner. The H1 receptor-mediated facilitation of NMDAR current response observed in this study is highly likely to occur in the presence of ambient histamine that might be released from histaminergic nerve terminals in the CA1 region, because pyrilamine and cetirizine attenuated NMDAR-mediated EPSC in the absence of exogenously applied H1 receptor agonists. Furthermore, the finding that H1 receptor agonists, histamine and 2-PEA, did not alter both NMDAR-mediated EPSC (see Fig. S1 B and C) and exogenous NMDA-induced current (see Fig. S3B) lends further support for the notion that H1 receptors in the hippocampus are activated by tonic release of histamine or constitutive activity of H1 receptors (see Fig. 7). In fact, histamine-containing nerve fibers originating from the tuberomammillary nucleus have been shown to project to the CA1 and CA3 (Inagaki et al., 1988). Recently, Cabay et al. (2018) have reported that extracellular concentration of histamine in CA1 of hippocampal slices was 2.8 μM at 2–6 h after slicing with high variability and significant decrease of its concentration as compared to that at 0–2 h. Thus, it seems that ambient histamine endogenously released in hippocampal slices could be enough to stimulate H1 receptors to modulate glutamatergic synapses. This could explain the observation in this study that exogenously applied histamine did not affect both the NMDAR component of EPSCs and LTP at Shaffer collateral-CA1 pyramidal neuron synapses (see Figs. S1B and C and Fig. S3B).