Improvement in Fear Memory by Histamine-Elicited ERK2 Activation in Hippocampal CA3 Cells

Abstract

Consolidation of associative memories appears to require extracellular signal-related kinase2 (ERK2) activation, which is modulated by several factors, including neurotransmitter receptor stimulation. Here we show that in vitro stimulation of either H2 or H3 histaminergic receptors activates ERK2 in hippocampal CA3 pyramidal cells. In behaving animals, bilateral posttraining injections into the dorsal hippocampus of histamine H2 or H3 receptor agonists improve memory consolidation after contextual fear conditioning. Local administration of U0126, a selective inhibitor of ERK kinase, prevents memory improvements exerted by the agonists, without causing any behavioral effect per se. This is the first evidence of a positive correlation between ERK phosphorylation and memory improvement. Moreover, we demonstrate that the brain histaminergic system regulates hippocampal ERK cascade. Finally, our data indicate that early ERK2 hippocampal activation is not required for the expression of long-term fear memories.

The histamine H3-receptor inverse agonist Pitolisant improves fear memory in mice

“…Thioperamide microinjected in the BLA impairs consolidation of fear memory in rats [32]. Procognitive effects are observed in the fear conditioning paradigm when H 3 R of the BLA or the hippocampus are activated rather than blocked [32][33][34], an observation opposite to the results obtained after systemic injections of thioperamide or Pitolisant (Charlier and Tirelli [14]; present results). Many studies have shown that the NBM plays a central role in memory consolidation of information acquired in the fear conditioning task [6,35].…”

The H3 receptor protean agonist proxyfan enhances the expression of fear memory in the rat

“…Proxyfan behaves as a protean agonist, as it shows a spectrum of activities that range from full agonist to full inverse agonist at distinct functional responses within different animal species. In the learning paradigm used in the present study, contextual fear conditioning, proxyfan mimicked the memory-enhancing effect of H 3 receptor agonists administered locally either in the amygdala (Cangioli et al, 2002), or in the hippocampus (Giovannini et al, 2003) in contextual fear conditioning. Accordingly, rats that received systemic administrations of proxyfan showed a stronger response to the footshock-context association, as they spent more time freezing in the retention test.…”

“…For instance, post-training administrations of the H 3 receptor antagonists/inverse agonists thioperamide or clobenpropit into the basolateral amygdala impair memory for aversive events (Passani et al, 2001), whereas agonists such as R-a-methylhistamine improve the expression of fear memory after contextual fear conditioning (Cangioli et al, 2002). In the same learning paradigm, post-training injections into the dorsal hippocampus of R-a-methylhistamine improve memory consolidation (Giovannini et al, 2003). Almost invariably, the behavioural effects of histaminergic compounds have been studied following systemic or local administration into small brain regions, which are known to be crucial for the behavioural response under study.…”

Aversive memory reactivation engages in the amygdala only some neurotransmitters involved in consolidation

“…We previously reported that unoperated and postconditioning ketamine-anesthetized rats that received intracerebral saline injections exhibited similar freezing responses to TC (Sacchetti et al 1999;Giovannini et al 2003), thus suggesting that these manipulations do not interfere with consolidation. Ketamine-anesthetized animals display frequency-specific receptive field plasticity induced by Pavlovian fear conditioning (Lennartz and Weinberger 1992).…”