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

Abstract

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.

A Single Dose of Lysergic Acid Diethylamide Influences Gene Expression Patterns within the Mammalian Brain

“…Arc protein and mRNA are both specifically localized to dendrites, and arc is predicted to be involved in cytoskeletal rearrangements during the process of synaptic plasticity (Lyford et al 1995). Consistent with this interpretation, antisense inhibition of arc expression leads to impairment of the maintenance phase, but not the induction, of long-term potentiation (Guzowski et al 2000). LSD produced a robust fivefold increase in arc expression in the prefrontal cortex, similar to that seen with the hallucinogenic drug 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (Pei et al 2000;Tilakaratne and Friedman 1996).…”

Relapse to cocaine seeking increases activity-regulated gene expression differentially in the prefrontal cortex of abstinent rats

“…In a recent study, greater Fos immunoreactivity was also detected in the medial PFC, OFC, and striatum of abstinent rats that were re-exposed to the cocaine-associated chamber when compared to rats that underwent explicit extinction training (Zavala et al 2007). Activity-regulated genes contribute to the promotion and maintenance of synaptic plasticity (Lu 2003, Rial Verde et al 2006, associative learning , Liu et al 2004, Malkani et al 2004, and long-term storage and retrieval of memories (Guzowski et al 2000;Hall et al 2001;Thomas et al 2002;Bozon et al 2003;Davis et al 2003;Liu et al 2004;Plath et al 2006). Furthermore, manipulation of BDNF levels in the brain alters cocaine seeking (Horger et al 1999;Lu et al 2004;Berglind et al 2007;Graham et al 2007).…”

“…Additionally, early phases of instrumental learning (Hernandez et al 2006;Kelly and Deadwyler 2003) elicit widespread zif/268 and arc induction throughout an extensive corticostriatal network in rats. Furthermore, knockdown of c-fos, zif/268, arc, or tissue plasminogen activator (tPA) that cleaves proBDNF to mature BDNF impairs longterm memory consolidation (Calabresi et al 2000, Guzowski et al 2000Fleischmann et al 2003;Jones et al 2001 and produces deficits in drug-induced conditioned place preference (Valjent et al 2006). …”

Mapping neuronal activation and the influence of adrenergic signaling during contextual memory retrieval

“…Arc (Lyford et al 1995), also termed Arg3.1 (Link et al 1995), is an activityregulated, cytoskeleton-associated protein implicated in synaptic plasticity and memory (Steward et al 1998;Guzowski et al 2000). Basal expression of Arc is very low in most neurons.…”

“…Second, the hippocampus is critical for contextual memory storage and discrimination of contexts during memory retrieval Phillips and LeDoux 1992;Holt and Maren 1999). Third, antisense knock-down of Arc expression in the hippocampus reduces the expression of long-term potentiation and spatial memory (Guzowski et al 2000). This is likely due to a role for Arc in consolidation because short-term synaptic plasticity and short-term memory remain intact.…”