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    • caspofungin Evidence indicates that astrocytes play a role i

    2022-09-29

    Evidence indicates that astrocytes play a role in the modulation of NMDAR activity in the CA1 (Henneberger et al., 2010; Papouin et al., 2017a, Papouin et al., 2017b; Robin et al., 2018). Therefore, we sought to examine whether astrocytes are involved in the H1 receptor antagonist/inverse agonist-induced attenuation of NMDAR-mediated synaptic excitation. To test this, we first examined the effect of the glial caspofungin inhibitor, FAC (Swanson and Graham, 1994; Fonnum et al., 1997), on the NMDAR activity. As illustrated in Fig. 3A and B, FAC treatment (5 mM) caused a gradual decrease in the amplitude of NMDAR-mediated EPSC [F(2,12) = 53.666, p < 0.001, n = 5], and the effect of FAC persisted for more than 60 min during its treatment. Pretreatment of slices with D-serine (100 μM) markedly rescued the FAC-induced decrease in the NMDAR-mediated EPSC amplitude (p = 0.048, n = 5; Fig. 3A and B). When FAC (5 mM) was continuously treated, addition of pylilamine (0.1 μM) and cetirizine (10 μM) did not produce any further changes in NMDAR-mediated EPSCs [F(2,15) = 0.846, p = 0.449, n = 6; Fig. 3C and D]. D-Serine is released from astrocytes and can enhance NMDAR-mediated EPSCs in CA1 pyramidal neurons (Henneberger et al., 2010). D-serine treatment prevented the FAC-induced attenuation of NMDAR-mediated EPSCs; therefore, we reasoned that FAC would inhibit the liberation of D-serine from astrocytes, which, in turn, suppressed the enhancement of NMDAR-mediated EPSCs by D-serine, resulting in the suppression of NMDAR-mediated EPSCs. Perfusion of 100 μM D-serine significantly increased NMDAR-mediated EPSC amplitude in CA1 pyramidal neurons [t(8) = −2.846, p = 0.019, n = 5; Fig. 4A and B]. Exogenous D-serine occluded the effects of H1 receptor antagonist/inverse agonists on NMDAR-mediated EPSCs; in fact, pyrilamine (0.1 μM) and cetirizine (10 μM) did not significantly alter the D-serine (100 μM)-induced enhancement of NMDAR-mediated EPSCs [F(2,15) = 1.163, p = 0.339, n = 6; Fig. 4C and D]. We finally sought to determine whether the H1 receptor-induced modulation of NMDAR activity is functionally associated with NMDAR-mediated synaptic plasticity in the CA1. We examined the effects of the H1 antagonist/inverse agonists on LTP at excitatory synapses between Schaffer collaterals and CA1 pyramidal neurons. HFS given to Schaffer collaterals markedly enhanced the fEPSP slope recorded in the CA1. Perfusion of either 0.1 μM pyrilamine [U(12) = 3.000, p = 0.004, n = 7] or 10 μM cetirizine [U(8) = 1.000, p = 0.016, n = 5] significantly attenuated the HFS-induced enhancement of fEPSP slope (Fig. 5). In addition, facilitation of fEPSP during the last 15 min of recording in the pyrilamine treated group [H(3) = 14.314, p = 0.025 vs 0–15 min before HFS] was weaker than that in the control group [p = 0.003 vs 0–15 min before HFS]. Facilitation of fEPSP in the cetirizine treated group [H(3) = 16.280, p = 0.097 vs 0–15 min before HFS] was also weaker than that in the control group [p = 0.020 vs 0–15 min before HFS]. By contrast, application of D-serine significantly augmented the HFS-induced enhancement of fEPSP slope [U(8) = 3.000, p = 0.004, n = 5; Fig. 6A and C]. Facilitation of fEPSP during the last 15 min of recording in the D-serine treated group [H(3) = 13.904, p = 0.004 vs 0–15 min before HFS] was more pronounced than that in the control group [p = 0.027 vs 0–15 min before HFS]. In the presence of 100 μM D-serine, pyrilamine did not cause any further significant effect on the HFS-induced enhancement of fEPSP slope (U = 8.000, p = 0.421, n = 6; Fig. 6B and C). Facilitation of fEPSP during the last 15 min of recording in pyrilamine plus D-serine treated group [H(3) = 14.749, p = 0.010 vs 0–15 min before HFS] was almost equivalent to that in the D-serine treated group [p = 0.017 vs 0–15 min before HFS]. The findings are consistent with the notion that the H1 receptor antagonist/inverse agonists, pyrilamine and cetirizine, decreased the induction of LTP at CA1 excitatory synapses in a manner sensitive to the NMDAR enhancer, D-serine.