Histamine receptor expression, hippocampal plasticity and ammonia in histidine decarboxylase knockout mice

Abstract

Genetic ablation of the histamine producing enzyme histidine decarboxylase (HDC) leads to alteration in exploratory behaviour and hippocampus-dependent learning. We investigated how brain histamine deficiency in HDC knockout mice (HDC KO) affects hippocampal excitability, synaptic plasticity, and the expression of histamine receptors. No significant alterations in: basal synaptic transmission, long-term potentiation (LTP) in the Schaffer collateral synapses, histamine-induced transient changes in the CA1 pyramidal cell excitability, and the expression of H1 and H2 receptor mRNAs were found in hippocampal slices from HDC KO mice. However, when compared to WT mice, HDC KO mice demonstrated: 1. a stronger enhancement of LTP by histamine, 2. a stronger impairment of LTP by ammonia, 3. no long-lasting potentiation of population spikes by histamine, 4. a decreased expression of H3 receptor mRNA, and 5. less potentiation of population spikes by H3 receptor agonism. Parallel measurements in the hypothalamic tuberomamillary nucleus, the origin of neuronal histamine, demonstrated an increased expression of H3 receptors in HDC KO mice without any changes in the spontaneous firing of "histaminergic" neurons without histamine and their responses to the H3 receptor agonist (R)-α-methylhistamine. We conclude that the absence of neuronal histamine results in subtle changes in hippocampal synaptic transmission and plasticity associated with alteration in the expression of H3 receptors.

Fig. 1

Histamine-deficient mice show no abnormalities in basal synaptic transmission and synaptic plasticity in the Schaffer collaterals–CA1 pathway. a representative examples of stimulus—response relationships in hippocampal slices from WT and KO mice; each trace represents the average of three responses to the stimulus at 2, 4, and 6 V, respectively. b Summary of averaged Schaffer collateral–CA1 field EPSPs evoked at increasing intensities as shown in (a). c time course of LTP induced by high frequency stimulation (HFS, 2 trains of 100 stimuli at 100 Hz). d Time course of LTP induced by moderate theta-burst stimulation (TBS, ten bursts of five stimuli at 100 Hz and test intensity separated by 200 ms intervals)

Fig. 2

Histamine significantly enhances LTP induced by weak TBS in HDC KO, but not WT mice. a The time course of LTP in control and histamine-treated slices in WT. b The time course of LTP in control and histamine-treated slices in KO mice. Histamine (10 μM) was applied 10 min before and washed out 5 min after weak TBS as indicated by black bars. *P < 0.05, **P < 0.01 Student’s t test

Fig. 3

Ammonia causes more severe impairment of hippocampal LTP in histamine deficient mice (HDC KO). a The time course of changes in fEPSP amplitude in the CA1 area after HFS of Schaffer collaterals in control and ammonia-treated hippocampal slices from WT. b The time course of changes in fEPSP amplitude in the CA1 area after HFS of Schaffer collaterals in control and ammonia-treated hippocampal slices from HDC KO mice. c the mean magnitude of potentiation at 80–90 min postHFS in control and ammonia-treated slices from WT and KO mice. *P = 0.033, ***P < 0.0001

Fig. 4

Histamine effects on population spikes (PS) in HDC KO and WT mice. The time course of changes in the amplitude of PS during and after perfusion with 10 μM histamine (HA, marked by open bar). A long lasting enhancement is observed in WT, whereas the potentiation gives way to a long lasting depression of PS about 20 min after washout in KO. The mean amplitudes of responses at minutes 40–50 after histamine washout are significantly different (***P = 0.0007)

Fig. 5

Histamine equally blocks slow afterhyperpolarizations in HDC KO and WT mice. Representative traces (left) and the mean amplitude of AHPs in control and in the presence of histamine (5 μM) or the H2 receptor agonist impromidine (3 μM) (right). Bottom the time course of changes in the AHP amplitude in one representative cell

Fig. 6

Effects of pharmacological activation and blockade of H3 histamine receptors on population spike (PS) amplitude in hippocampal slices from HDC KO and WT mice. a, b Time course of changes in the amplitude of PS during and after 10 min perfusion with the H3 receptor agonist (R)-α-methylhistamine ((R)-α-MeHA, 2 µM) and 20 min perfusion with the H3 receptor antagonist thioperamide (TPA, 10 μM), respectively. The periods of applications are marked by open bars. The mean amplitudes of population spike responses at minutes 50–60 after (R)-α-MeHA washout are significantly different (*P = 0.040), indicating less potentiation in the KO hippocampus

Fig. 7

Expression and function of histamine receptors in the tuberomamillary nucleus of HDC knockout and wild type mice. a Expression of H1, H2, and H3 histamine receptor transcripts in the TMN as well as comparison of spontaneous firing frequencies of TMN histaminergic neurons from HDC WT and KO mice. b Schematic drawing of coronal slice illustrating the location of histaminergic cells (marked by dots) and recording site in the ventrolateral TMN. Below action potential, recorded in cell-attached mode (average of 12 individual traces) of the WT histaminergic neuron and example of its typical regular firing. c Inhibition of firing of TMN neurons by the H3R agonist (R)-α-methylhistamine at 2 μM (period of application is marked by bar)