Endogenous histamine facilitates long-term potentiation in the hippocampus during walking

Abstract

Long-term potentiation (LTP) in hippocampal CA1 depends on the behavioral state of LTP induction. We hypothesize that histaminergic activity in the septohippocampal system, which is active during walking compared with other behavioral states, is responsible for the behavioral dependence of LTP. Field basal-dendritic EPSPs of CA1 pyramidal cells were recorded in freely behaving rats, and LTP was induced by a single 200 Hz stimulation train (0.5 s duration). Basal-dendritic LTP was facilitated when induced during walking compared with awake immobility (IMM) or rapid-eye-movement sleep. The facilitation of basal-dendritic LTP during walking was abolished by lesion of tuberomammillary nucleus (TMN) neurons with orexin-saporin or by intramedial-septal infusion of the H(1) histaminergic blocker triprolidine but not the H(2) histaminergic blocker cimetidine. Conversely, histamine infusion in the medial septum enhanced the basal-dendritic LTP induced during IMM to a magnitude similar to that induced during walking. Basal-dendritic LTP induced during walking was not further enhanced by intraseptal histamine infusion. Combined with the previous result that behavior-dependent LTP is mediated by cholinergic septohippocampal neurons, we conclude that the facilitation of basal-dendritic LTP in CA1 during walking was mediated by TMN histaminergic afferents acting on H(1) receptors in the medial septum, which may then enhance cholinergic and noncholinergic inputs to the hippocampus.

Figure 1.

Recording of hippocampal basal-dendritic evoked potentials in CA1 and intraseptal cannula. A–C, Representative coronal sections showing locations of electrodes and cannula. A, Anterior pair of hippocampal electrodes, L1 and L2 at P3.2, L1.7; B, the posterior electrode pair L3 and L4 at P4.6, L2.8. C, Section showing a cannula track through the medial septum, with arrow indicating the end of the track. D, Representative basal-dendritic average fEPSPs evoked by cathodal stimulation of L2 and recorded with reversed polarity across L3 and L4 electrodes; shock artifacts are labeled by filled dots. E, F, EEG from L3 and L4 electrodes recorded around the time of application of the high-frequency stimulus train [tetanus (Tet)] for inducing LTP, during walking (E) and REMS (F); a theta rhythm accompanied both walking and REMS.

Figure 2.

ADA-immunoreactive (ADA-ir) neurons in the TMN in representative orexin–saporin (Ore-SAP) lesion and sham lesion rats. Coronal section through the TMN of sham lesion rats (A–C) and lesion rats with orexin–saporin infusion into the TMN (D–F). 3 v, Third ventricle. Scale bar, 0.25 mm. G, Number of ADA-immunoreactive neurons in sections through the TMN was significantly decreased (*p < 0.0001, Student's t test) in orexin–saporin-treated rat (n = 9) compared with sham lesion rats (n = 8).

Figure 3.

Histaminergic lesion in the tuberomammillary nucleus abolished the difference in hippocampal basal-dendritic LTP induced during walking and REMS. A, B, fEPSP traces at the basal-dendritic electrode of representative rats at 0 (baseline), 30, 60, and 180 min after tetanus in sham lesion rats (A) and orexin–saporin (Ore-SAP) lesion rats (B). To facilitate comparison, the fEPSPs were scaled to make the peak amplitudes of the baseline response appear identical in A and B. C, D, Normalized fEPSP slopes (mean ± SEM), induced during walking (Walk) or REMS, plotted versus time after LTP-inducing tetanus for sham lesion rats (C) and orexin–saporin lesion rats (D). A two-way (behavioral state × time) repeated-measures ANOVA revealed a significant effect of behavioral state (walking vs REMS) on LTP of the sham lesion rat (p = 0.0064) but not in the orexin–saporin TMN lesion rats (p = 0.66).

Figure 4.

Positive correlation between the number of ADA-immunoreactive (ADA-ir) neurons and the ratio of LTP during walking to that during REMS (walk/REMS LTP ratio) at 60 min (A) and 120 min (B) after tetanus. A positive correlation was found between the number of ADA-immunoreactive neurons and the walk/REMS LTP ratio. Correlation coefficient of r = 0.63 at 60 min (p = 0.007) and r = 0.54 at 120 min (p = 0.02); n = 17 including both orexin–saporin lesion (filled squares) and sham (open squares) rats.

Figure 5.

Walking-associated enhancement of LTP was attenuated by intraseptal administration of the H₁ histaminergic blocker triprolidine but not the H₂ histaminergic blocker cimetidine. A, B, Traces of fEPSP at the basal-dendritic electrode of representative rats at 0 (baseline), 30, 60, and 180 min after tetanus, with tetanus given during walking at 10 min after intraseptal administration of either triprolidine or saline (A) and either cimetidine or saline (B). The fEPSPs were scaled to make the peak amplitudes of the baseline response appear identical in A and B. C, D, Normalized fEPSP slopes (mean ± SEM), with LTP induced during walking after intraseptal administration of either saline or triprolidine (C) and saline or cimetidine (D). A two-way (treatment × time) repeated-measures ANOVA revealed a significant effect of triprolidine (p < 0.05) but not cimetidine (p = 0.43). no-tet, No tetanus.

Figure 6.

Administration of histamine into the medial septum enhanced LTP induced during IMM but not during walking. A, B, fEPSP traces at the basal-dendritic electrode of representative rats at 0 (baseline), 30, 60, and 180 min after tetanus, with tetanus given 10 min after intraseptal administration of either saline or histamine and LTP induced during IMM (A) and walking (B). The fEPSPs were scaled to make the peak amplitudes of the baseline response appear identical in A and B. C–D, Normalized fEPSP slopes (mean ± SEM), with LTP induced after intraseptal administration of either saline or histamine during IMM (C) and walking (D). A two-way (treatment × time) repeated-measures ANOVA revealed a significant effect of histamine versus saline when LTP was induced during IMM (p < 0.01) but not during walking (p = 0.56). no-tet, No tetanus.