Endogenous Histamine Facilitates Long-Term Potentiation in the Hippocampus during Walking

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.