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Inhibition of Activity-Dependent Arc Protein Expression in the Rat Hippocampus Impairs the Maintenance of Long-Term Potentiation and the Consolidation of Long-Term Memory

John F. Guzowski¹, Gregory L. Lyford², Gail D. Stevenson³, Frank P. Houston³, James L. McGaugh¹, Paul F. Worley², and Carol A. Barnes³

¹ Center for the Neurobiology of Learning and Memory and Department of Neurobiology and Behavior, University of California, Irvine, California 92697-3800, ² Departments of Neuroscience and Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, and ³ Departments of Psychology and Neurology and Division of Neural Systems, Memory, and Aging, University of Arizona, Tucson, Arizona 85724-5115

It is widely believed that the brain processes information and stores memories by modifying and stabilizing synaptic connections between neurons. In experimental models of synaptic plasticity, such as long-term potentiation (LTP), the stabilization of changes in synaptic strength requires rapid de novo RNA and protein synthesis. Candidate genes, which could underlie activity-dependent plasticity, have been identified on the basis of their rapid induction in brain neurons. Immediate-early genes (IEGs) are induced in hippocampal neurons by high-frequency electrical stimulation that induces LTP and by behavioral training that results in long-term memory (LTM) formation. Here, we investigated the role of the IEG Arc (also termed Arg3.1) in hippocampal plasticity. Arc protein is known to be enriched in dendrites of hippocampal neurons where it associates with cytoskeletal proteins (Lyford et al., 1995). Arc is also notable in that its mRNA and protein accumulate in dendrites at sites of recent synaptic activity (Steward et al., 1998). We used intrahippocampal infusions of antisense oligodeoxynucleotides to inhibit Arc protein expression and examined the effect of this treatment on both LTP and spatial learning. Our studies show that disruption of Arc protein expression impairs the maintenance phase of LTP without affecting its induction and impairs consolidation of LTM for spatial water task training without affecting task acquisition or short-term memory. Thus, Arc appears to play a fundamental role in the stabilization of activity-dependent hippocampal plasticity.

Key words: neuron; synaptic plasticity, long-term potentiation; long-term memory; hippocampus; oligodeoxynucleotide; immediate-early; gene; spatial memory

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20113993-09$05.00/0

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