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Arc localization to the nucleus regulates synaptic strength, homeostatic plasticity, and PML-dependent GluA1 transcription

  • Author(s): Korb, Erica
  • Advisor(s): Jan, Lily
  • et al.
Abstract

The activity-regulated cytoskeletal protein Arc/Arc3.1 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 in vivo and in vitro, Arc nuclear import and export is regulated by synaptic activity. 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 PML 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 PML levels, and decreasing GluA1 transcription, ultimately downscaling synaptic strength.

Similar to homeostatic downscaling, another form of plasticity, long term depression (LTD), also requries transcription and a decrease in synaptic strength. We found that stimuli that result in LTD results in a rapid and robust increase in Arc/Arg3.1 expression in the nucleus both in situ and in vitro. This localization requires active import and both the MEK/ERK and Ca2+/Calmodulin pathways. Arc/Arg3.1 is required for the transcriptional changes observed after chem-LTD induction. Arc/Arg3.1 expression in the nucleus occludes the late phase of chemical LTD (chem-LTD). In Arc knock out neurons, Arc/Arg3.1 expression in the nucleus is required for complete rescue of chem-LTD. Thus, in response to LTD inducing stimuli Arc/Arg3.1 translocates to the nucleus, regulates transcription of multiple genes, and through its actions in the nucleus mediates the late phase of LTD.

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