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.

Modulation of behavior by the histaminergic system: Lessons from HDC-, H3R- and H4R-deficient mice

“…However, in contradiction to the findings of Liu et al (2007), basal hippocampal excitability and LTP were not significantly different between Hdc −/− and wild-type mice (Chepkova et al, 2012). This discrepancy may be caused by the fact that Liu et al (2007) analyzed population spikes (PS), while Chepkova et al (2012) recorded field excitatory postsynaptic potentials (fEPSPs). 2.…”

“…A role of histamine in the hippocampus is further supported by the results reported by Chepkova et al (2012). However, in contradiction to the findings of Liu et al (2007), basal hippocampal excitability and LTP were not significantly different between Hdc −/− and wild-type mice (Chepkova et al, 2012).…”

“…However, this result was not reflected on protein level, since binding experiments with [ 3 H]tiotidine yielded a similar number of binding sites in the brains of wild-type and Hdc −/− mice (Fitzsimons et al, 2001). H 3 R mRNA was also decreased in the hippocampus and increased in the TM of Hdc −/− mice (Chepkova et al, 2012).…”

“…Even the neuronal structure of the TM was preserved (Parmentier et al, 2002). Analysis of mRNA expression showed only a non-significant trend toward increased H 1 R-and H 2 R expression in the hippocampus of Hdc −/− mice (Chepkova et al, 2012). By contrast, another study reports that H 2 R mRNA was reduced in the brain of Hdc −/− mice (Fitzsimons et al, 2001).…”

Donepezil, an acetylcholine esterase inhibitor, and ABT-239, a histamine H3 receptor antagonist/inverse agonist, require the integrity of brain histamine system to exert biochemical and procognitive effects in the mouse

“…The present findings indicate that H 3 R antagonists require the physiological release of histamine to exert their presynaptic and/or postsynaptic effects, and exclude the involvement of constitutively active H 3 Rs. Incidentally, the fact that both HDC-KO and a-FMHis treated mice responded in a comparable manner excludes the possibility that our observation were due to a reduction of H 3 R mRNA expression in the hippocampus of HDC-KO mice (Chepkova et al, 2012), or to decreased attention, waking or novelty induced arousal (Parmentier et al, 2002).…”