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The Journal of Neuroscience, March 15, 2002, 22(6):2054-2062

Long-Term Depression in the Adult Hippocampus In Vivo Involves Activation of Extracellular Signal-Regulated Kinase and Phosphorylation of Elk-1

Edda Thiels^{1, 2}, Beatriz I. Kanterewicz¹, Eric D. Norman^{1, 2}, James M. Trzaskos³, and Eric Klann^{1, 2}

¹ Department of Neuroscience and ² Center for the Neural Basis of Cognition, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, and ³ DuPont Pharmaceuticals Research Laboratory, Wilmington, Delaware 19880

Protein kinase cascades likely play a critical role in the signaling events that underlie synaptic plasticity and memory. The extracellular signal-regulated kinase (ERK) cascade is suited well for such a role because its targets include regulators of gene expression. Here we report that the ERK cascade is recruited during long-term depression (LTD) of synaptic strength in area CA1 of the adult hippocampus in vivo and selectively impacts on phosphorylation of the nuclear transcription factor Elk-1. Using a combination of in vivo electrophysiology, biochemistry, pharmacology, and immunohistochemistry, we found the following: (1) ERK phosphorylation, including phosphorylation of nuclear ERK, and ERK phosphotransferase activity are increased markedly, albeit transiently, after the induction of NMDA receptor-dependent LTD at the commissural input to area CA1 pyramidal cells in the hippocampus of anesthetized adult rats; (2) LTD-inducing paired-pulse stimulation fails to produce lasting LTD in the presence of the ERK kinase inhibitor SL327, which suggests that ERK activation is necessary for the persistence of LTD; and (3) ERK activation during LTD results in increased phosphorylation of Elk-1 but not of the transcription factor cAMP response element-binding protein. Our findings indicate that the ERK cascade transduces signals from the synapse to the nucleus during LTD in hippocampal area CA1 in vivo, as it does during long-term potentiation in area CA1, but that the pattern of coupling of the ERK cascade to transcriptional regulators differs between the two forms of synaptic plasticity.

Key words: long-term depression; extracellular signal-regulated kinase; mitogen-activated protein kinase; NMDA; cAMP response element-binding protein; Elk-1; protein phosphorylation; transcription factors

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Copyright © 2002 Society for Neuroscience  0270-6474/02/2262054-09$05.00/0

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