Improvement in fear memory by histamine-elicited ERK2 activation in hippocampal CA3 cells - PubMed (original) (raw)

Improvement in fear memory by histamine-elicited ERK2 activation in hippocampal CA3 cells

Maria Grazia Giovannini et al. J Neurosci. 2003.

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.

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Figures

Figure 1.

Figure 1.

Histamine and histamine agonists activate ERK cascade in rat hippocampal slices. a-j, Representative photomicrographs for p-ERK immunoreactivity in hippocampal slices. Sections in the bottom row show corresponding CA3 regions at higher magnification. ERK activation occurred exclusively in both dendrites and cell bodies of CA3 pyramidal cells. Scale bars: a-e, 1 mm; f, g, j, 750 μm; i, 200 μm; h, 75 μm. k, Summary histograms showing the number of neurons staining positive for p-ERK in shams (n = 9) and in slices treated with 0.1 μ

m

histamine (n = 4), 1 μ

m

MHPN (n = 3), 0.1 μ

m

amthamine (n = 10), 0.01 μ

m

immepip (n = 3), and 0.1 μ

m

RAMH (n = 10). Shown are means ± SEM. ***p < 0.001 versus sham (ANOVA and Newman-Keuls multiple comparison test). l, Densitometric analysis for p-ERK2 activation in sham (n = 11) and 0.1 μ

m

histamine-treated slices (n = 6); representative Western blots of p-ERK immunoreactivity are displayed in the bottom panel. Increase was selective for p-ERK2, because p-ERK1 immunoreactivity was not significantly changed with different treatments. No changes in total ERK amount were observed. Shown are means ± SEM. ***p < 0.001 versus sham (Student's t test).

Figure 2.

Figure 2.

Amthamine and RAMH activate the ERK cascade in rat hippocampal slices. Densitometric analysis for p-ERK2 activation in shams (n = 11) and in 0.1 μ

m

amthamine-treated (n = 5) and 0.1 μ

m

RAMH-treated (n = 5) slices; representative Western blots of p-ERK immunoreactivity are displayed in the bottom panel. Increase was selective for p-ERK2, because p-ERK1 immunoreactivity was not significantly changed with different treatments. No changes in total ERK amount were observed. Shown are means ± SEM. *p < 0.05 versus sham (ANOVA and Newman-Keuls multiple comparison test).

Figure 3.

Figure 3.

Influence of zolantidine and thioperamide (THIOPERAM) on histamine receptor-elicited increase of p-ERK immunoreactivity in hippocampal slices. Neurons staining positive for p-ERK in hippocampi of shams (n = 9), 5 μ

m

zolantidine (n = 3), 100 n

m

thioperamide (n = 13), 0.1 μ

m

histamine (n = 4), 0.1 μ

m

histamine plus 5 μ

m

zolantidine (n = 5), 0.1 μ

m

histamine plus 100 n

m

thioperamide (n = 6), 0.1 μ

m

histamine plus 5 μ

m

zolantidine plus 100 n

m

thioperamide (n = 6), 0.1 μ

m

amthamine (n = 10), 0.1 μ

m

amthamine plus 5 μ

m

zolantidine (n = 6), 0.01 μ

m

immepip (n = 3), and 0.01 μ

m

immepip plus 100 n

m

thioperamide (n = 9). Shown are means ± SEM. **p < 0.01 and ***p < 0.001 versus sham; ###p < 0.001 versus 0.1 μ

m

histamine; +p < 0.05 versus 0.1 μ

m

amthamine; $p < 0.001 versus 0.01 immepip (ANOVA and Newman-Keuls multiple comparison test).

Figure 4.

Figure 4.

TTX sensitivity of amthamine- and RAMH-elicited increase of p-ERK immunoreactivity in hippocampal slices. Neurons staining positive for p-ERK in hippocampi of shams (n = 9), 0.1 μ

m

amthamine (n = 10), 0.1 μ

m

amthamine plus 1 μ

m

TTX (n = 16), 0.1 μ

m

RAMH (n = 10), and 0.1 μ

m

RAMH plus 1 μ

m

TTX (n = 8). Shown are means ± SEM. *p < 0.05, **p < 0.01, and ***p < 0.001 versus sham (ANOVA and Newman-Keuls multiple comparison test).

Figure 5.

Figure 5.

Influence of U0126 on amthamine- or RAMH-elicited increase of p-ERK immunoreactivity in hippocampal slices. a-f, Representative photomicrographs for p-ERK immunoreactivity in hippocampal slices. Scale bar: a-c, 400 μm, d-f, 200 μm. g, Summary histograms show the number of neurons staining positive for p-ERK in controls (n = 16), in slices treated with 0.1 μ

m

amthamine alone (n = 10) or associated with 2 μ

m

U0126 (n = 3), and 0.1 μ

m

RAMH alone (n = 10) or associated with 2 μ

m

U0126 (n = 3). Shown are means ± SEM. ***p< 0.001 versus control (ANOVA and Newman-Keuls multiple comparison test).

Figure 6.

Figure 6.

Effects on contextual fear conditioning of posttraining bilateral injection of amthamine, RAMH, and U0126 into the hippocampus. Immediately after training, rats were injected with 1 μl/side under general anesthesia. One microliter of a 10 μ

m

solution of RAMH corresponded to a total amount of 1.25 ng, and 1 μl of a 1 μ

m

solution of amthamine corresponded to 0.16 ng. Seventy-two hours after training, freezing was measured during the 6 min test period in unoperated controls (n = 10), saline-injected controls (n = 9), rats injected with 2 μg of U0126 (n = 12), 0.16 ng of amthamine (n = 12), 0.16 ng of amthamine plus 2 μg of U0126 (n = 12), 1.25 ng of RAMH (n = 10), and 1.25 ng of RAMH plus 2 μg of U0126 (n = 12). Shown are means ± SEM. *p < 0.05 versus unoperated and saline-injected control; #_p_ < 0.05 versus amthamine; p < 0.01 versus RAMH (ANOVA and Newman-Keuls multiple comparison test).

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