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

Abstract

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.

Flavonoids as modulators of memory and learning: molecular interactions resulting in behavioural effects

“…For example, the activity-regulated cytoskeletal-associated protein (Arc/Arg3.1), whose expression is known to be dependent on Akt-mammalian target of rapamycin activation, was found to regulate a-amino-3-hydroxy-5-methyllisoxazole-4-propionic acid receptor trafficking (103) . In agreement with this, the expression of Arc/Arg3.1 was shown to facilitate changes in synaptic strength and the induction of morphological changes, such as those dependent on actin-polymerisation (140,141) (Fig. 2(B)).…”

Class I Histone Deacetylase-mediated Repression of the Proximal Promoter of the Activity-regulated Cytoskeleton-associated Protein Gene Regulates Its Response to Brain-derived Neurotrophic Factor

“…Messaoudi et al (11) reported that Arc protein synthesis was required for BDNF-induced LTP. Furthermore, two waves of Arc induction have been observed after a single spatial exploration (19).…”

“…Arc mRNA has been detected in cell bodies, dendrites, and spines after stimulation (7,8), and the Arc protein could be synthesized locally at dendritic spines (9,10). Arc is known to be required for the endocytosis of AMPA receptors (10) and for long-term potentiation (LTP)-induced F-actin stabilization (9,11). Okuno et al (12) reported that Arc plays a role in the inverse synaptic tagging of silent synapses; Arc accumulated in silent synapses to reduce surface AMPA receptors (12).…”

BDNF-induced local protein synthesis and synaptic plasticity

“…Intrahippocampal infusion of BDNF resulted in the accumulation of Arc transcripts in dendrites and triggered long-term potentiation (BDNF-LTP) at medial perforant path-granule cell synapses in vivo (Messaoudi et al, 2007;Ying et al, 2002), and similar effects were observed in cultured cerebrocortical neurons (Rao et al, 2006), but the mechanisms involved have not been clarified. BDNF signaling induces the phosphorylation of ZBP1 and local synthesis of b-actin in growth cones, contributing to growth cone turning (Sasaki et al, 2010).…”