Spatial Exploration-InducedArcmRNA and Protein Expression: Evidence for Selective, Network-Specific Reactivation

Abstract

The immediate-early gene Arc is transcribed in neurons that are part of stable neural networks activated during spatial exploratory behaviors. Arc protein has been demonstrated to regulate AMPA-type glutamate receptor trafficking by recruiting endosomal pathways, suggesting a direct role in synaptic plasticity. The purpose of the present study is to examine the fidelity of Arc mRNA translation and the temporal dynamics of behaviorally induced Arc protein expression after rats explore a novel environment. These experiments reveal two waves of Arc protein expression after a single exploration session. In the initial wave, virtually all cells that express Arc mRNA in the hippocampus and parietal cortex also express Arc protein, indicating, at a cellular level, that mRNA transcription and translation are closely correlated from 30 min to 2 h in hippocampal CA and parietal neurons. A second wave of protein expression spans the interval from 8 to 24 h and is also remarkably specific to cells active in the original behavior-induced network. This second wave is detected in a subset of the original active network and displays the novel property that the proportions of Arc-positive neurons become correlated among regions at 24 h. This suggests that the second expression wave is driven by network activity, and the stabilization of circuits reflecting behavioral experience may occur in temporally discrete phases, as memories become consolidated. This is the first demonstration of network-selective translational events consequent to spatial behavior and suggests a role for immediate-early genes in circuitspecific, late-phase synaptic biology.

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). We previously demonstrated that the robust stimulation of TrkB with BDNF in cultured rat cortical cells induced the biphasic expression of Bdnf mRNA, which was observed 1-3 h (primary induction) and 24 -72 h (secondary induction) after the stimulation, and that this biphasic expression of Bdnf mRNA was accompanied by a similar expression profile for Arc mRNA (43).…”

“…It is important to note that the induction of Arc mRNA in the secondary phase was mediated by the binding of endogenously synthesized BDNF to TrkB, while the secondary induction of Bdnf mRNA was controlled in an activity-dependent manner (43). Therefore, the distinct usage of the SARE and the proximal Arc promoter may be involved in the control of two waves of Arc induction (19); the secondary wave of Arc synthesis could be mainly mediated by the interaction between secreted BDNF and TrkB under cellular conditions in which HDAC1-mediated repressive activity may have been released from the Arc promoter. Thus, BDNF-induced Arc expression could provide a clearer understanding of the molecular mechanisms underlying Arc-mediated long-lasting changes in neuronal functions in the brain.…”

“…On the other hand, evidence has accumulated to show that Arc expression is involved in the control of memory consolidation in accordance with the actions of BDNF (9, 16 -18). A previous study in rats reported two waves of Arc induction in the hippocampus after a single spatial exploration, the second one of which spanned the interval from 8 to 24 h post-exploration (19), and may involve the actions of BDNF in local translation at spines (9). However, it currently remains unclear how Arc expression is regulated by neuronal activity or BDNF in terms of synaptic plasticity.…”

Acute Stress and Nicotine Cues Interact to Unveil Locomotor Arousal and Activity-Dependent Gene Expression in the Prefrontal Cortex

“…Messenger RNA (mRNA) levels of the AP-1 transcription factor c-Fos are used as an early measure of altered neuronal metabolic activity (Finkbeiner and Greenberg 1998;Herdegen and Leah 1998). Like c-fos, detection of the immediate early gene arc can be used to indirectly assess levels of neuronal activity (Guzowski et al 2001;Ramirez-Amaya et al 2005). Unlike the transcription factor c-Fos, Arc mRNA and protein are targeted to activate dendrites in an N-methyl-D-aspartate (NMDA) receptor-dependent manner and Arc protein presumably exerts effects on postsynaptic electrophysiological properties through its interaction with the endocytic machinery trafficking alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (Fujimoto et al 2004;Steward and Worley 2001).…”

A threshold neurotoxic amphetamine exposure inhibits parietal cortex expression of synaptic plasticity-related genes

“…One commonality to the gene expression changes found in the present study is their relation to synaptic plasticity. ARC induction, in particular, has been implicated in the formation and strengthening of synaptic formation after NMDA receptor stimulation and learned behavior (Lyford et al, 1995;Guzowski et al, 2001;Steward and Worley, 2001;Ramirez-Amaya et al, 2005). In addition, NGFI-A (egr1, zif/268; (Cole et al, 1989;Wisden et al, 1990)) has been implicated in synaptic formation and learning (Wang et al, 1994;Wang et al, 1995), although it may not be as closely linked as ARC (Guzowski et al, 2001).…”