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The Journal of Neuroscience, September 26, 2007, 27(39):10445-10455; doi:10.1523/JNEUROSCI.2883-07.2007

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Cellular/Molecular
Sustained Arc/Arg3.1 Synthesis Controls Long-Term Potentiation Consolidation through Regulation of Local Actin Polymerization in the Dentate Gyrus In Vivo

Elhoucine Messaoudi, Tambudzai Kanhema, ^* Jonathan Soulé, ^* Adrian Tiron, ^* Girstaute Dagyte, Bruno da Silva, and Clive R. Bramham

Department of Biomedicine and Bergen Mental Health Research Center, University of Bergen, N-5009 Bergen, Norway

Correspondence should be addressed to Dr. Clive Bramham, Department of Biomedicine, University of Bergen, Jonas Lies vei 91, N-5009 Bergen, Norway. Email: clive.bramham{at}biomed.uib.no

New gene expression is necessary for long-term potentiation (LTP) consolidation, yet roles for specific activity-induced mRNAs have not been defined. Here we probed the dynamic function of activity-induced Arc (activity-regulated cytoskeletal-associated protein)/Arg3.1 (activity-regulated gene 3.1 protein homolog) mRNA using brief, local infusions of antisense (AS) oligodeoxynucleotides at multiple time points during dentate gyrus LTP in vivo. Surprisingly, early Arc synthesis is necessary for early expression of LTP, whereas sustained synthesis is required to generate stably modified synapses. AS application 2 h after LTP induction results in a rapid and permanent reversal of LTP. This reversal is associated with rapid knockdown of upregulated Arc, dephosphorylation of actin depolymerization factor/cofilin, and loss of nascent filamentous actin (F-actin) at synaptic sites. Infusion of the F-actin stabilizing drug jasplakinolide during LTP maintenance blocks the ability of AS to reverse LTP. These results couple activity-induced expression of Arc to expansion of the actin cytoskeleton underlying enduring LTP. Furthermore, Arc synthesis is required for both the induction and consolidation of LTP elicited by local BDNF infusion, thus identifying Arc as a key molecular effector of BDNF in synaptic plasticity.

Key words: synaptic plasticity; long-term potentiation; immediate early gene; protein synthesis; actin; brain-derived neurotrophic factor; neurotrophins; hippocampus

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Received Jan. 5, 2007; revised July 25, 2007; accepted Aug. 3, 2007.

Correspondence should be addressed to Dr. Clive Bramham, Department of Biomedicine, University of Bergen, Jonas Lies vei 91, N-5009 Bergen, Norway. Email: clive.bramham{at}biomed.uib.no

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