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The Journal of Neuroscience, October 8, 2003, 23(27):9016-9023

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Behavioral/Systems/Cognitive
Improvement in Fear Memory by Histamine-Elicited ERK2 Activation in Hippocampal CA3 Cells

Maria Grazia Giovannini,¹ Marcel Efoudebe,¹ Maria Beatrice Passani,¹ Elisabetta Baldi,² Corrado Bucherelli,² Filippo Giachi,¹ Renato Corradetti,¹ and Patrizio Blandina¹

¹Dipartimento di Farmacologia Preclinica e Clinica, Universitá di Firenze, 50139 Firenze, Italy, and ²Dipartimento di Scienze Fisiologiche, Universitá di Firenze, 50134 Firenze, Italy

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.

Key words: contextual fear conditioning; ERK1; ERK2; hippocampus; histamine; H₂ receptor; H₃ receptor; U0126

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Received Feb 27, 2003; revised July 22, 2003; accepted July 31, 2003.

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