Arc in the nucleus regulates PML-dependent GluA1 transcription and homeostatic plasticity

Abstract

The activity-regulated cytoskeletal protein Arc/Arg3.1 is required for long-term memory formation and synaptic plasticity. Arc expression is robustly induced by activity, and Arc protein localizes both to active synapses and the nucleus. While its synaptic function has been examined, it is not clear why or how Arc is localized to the nucleus. We found that murine Arc nuclear expression is regulated by synaptic activity in vivo and in vitro. We identified distinct regions of Arc that control its localization, including a nuclear localization signal, a nuclear retention domain, and a nuclear export signal. Arc localization to the nucleus promotes an activity-induced increase in promyelocytic leukemia nuclear bodies, which decreases GluA1 transcription and synaptic strength. Finally, we show that Arc nuclear localization regulates homeostatic plasticity. Thus, Arc mediates the homeostatic response to increased activity by translocating to the nucleus, increasing promyelocytic leukemia levels, and decreasing GluA1 transcription, ultimately downscaling synaptic strength.

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

“…This protein is upregulated by synaptic activity thereby controlling the degradation of Arc, a protein involved in AMPAR endocytosis (Greer et al, 2010). Arc protein is also involved in the mGluRdependent long-term depression through AMPAR endocytosis (Waung et al, 2008), and its nuclear localization regulates homeostatic plasticity by decreasing GluA1 transcription (Korb et al, 2013). Knockout mouse models for Ube3A have reduced hippocampal synaptic GluA1 receptors with a concomitant decrease in AMPAR mediated current, and reduced levels of mESPC (Greer et al, 2010).…”

Long-Term Abstinence from Developmental Cocaine Exposure Alters Arc/Arg3.1 Modulation in the Rat Medial Prefrontal Cortex

“…Thus, we hypothesize that the increased expression of Arc/Arg3.1 in the whole homogenate may depend not only on its enhancement in the crude synaptosomal fraction (Giannotti et al, 2013b) but also on the up-regulation herein observed in the nuclear fraction. Also, the increase of nuclear Arc/Arg3.1 might participate to the regulation of glutamate AMPA receptors since we observed reduced Gria1 transcription, which in turn may lead to reduced GluA1 synthesis, adding novel evidence to the inverse relationships existing between Arc/Arg3.1 and AMPA receptors following long-term cocaine withdrawal (Giannotti et al, 2013b;Korb et al, 2013).…”

“…4C). While these changes may contribute to explain Arc/Arg3.1 up-regulation, we next measured the transcription of Gria1, the main glutamate AMPA receptor subunit, a target of increased nuclear Arc/Arg3.1 expression (Korb et al, 2013). Indeed, we found reduced Gria1 mRNA levels (-21%, p<0.05) (Fig.…”

“…While there is no doubt that Arc/Arg3.1 mRNA is locally translated in dendrites and plays an important role in synaptic changes underlying plastic modifications necessary for long-term memory formation (Bramham et al, 2010;Shepherd and Bear, 2011), it must be taken into account that Arc/Arg3.1 protein is found not only in dendrites, but also at high levels in the nucleus (Bloomer et al, 2007;Korb et al, 2013). Thus, we hypothesize that the increased expression of Arc/Arg3.1 in the whole homogenate may depend not only on its enhancement in the crude synaptosomal fraction (Giannotti et al, 2013b) but also on the up-regulation herein observed in the nuclear fraction.…”

“…While initial studies showed a prominent localization of Arc/Arg3.1 at active synapses (Dynes and Steward, 2007) where it can be locally synthesized, recent lines of evidence have challenged this observation showing that Arc/Arg3.1 protein is also localized in inactive synapses where it can be accumulated (Okuno et al, 2012). Interestingly, Arc/Arg3.1 is present not only in dendrites (Korb et al, 2013;Bloomer et al, 2007) but also in the cell nucleus adding complexity, but perhaps also specificity, to its modulation, although the role of nuclear Arc/Arg3.1 is largely unknown.…”