From Where? Synaptic Tagging Allows the Nucleus Not to Care
Most of us now accept that the formation of long-lasting memories requires de novo transcription of plasticity-related proteins. It is also thought that localized translation of these transcripts, at or near recently activated synaptic sites, structurally stabilizes synaptic connections, thereby consolidating the memory. However, the molecular mechanisms underlying where, when, and how these newly synthesized transcripts participate in memory storage has remained a formidable question in neuroscience. Here we discuss the hypothesis that the nucleus acts as a calculator of incoming signals from activated synapses, either in the form of an electrical signal, through calcium, or as part of a transported signal. As long as a synaptic tag is created, the form of how a signal reaches the nucleus is freed from the requirement of leaving a “trail of breadcrumbs.” The nucleus can instead detect information on how the neuron fits into the network (counting number of modified or active synapses, or whether inhibitory neurons have a say, for example). We propose that it is the output of the nucleus, or nucleus-to-synapse signaling, along with the type of synaptic tag formed, that determines whether the right transcript will be translated at the right synapse at the right time. We further discuss the idea of inverse tagging and how local protein synthesis might play a role in distinguishing inactive versus active synapses.
KeywordsSynaptic tagging Action potentials Dendritic mRNA Arc/Arg3.1 Local protein synthesis
This research was funded by the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health.
- Ch’ng TH, Uzgil B, Lin P, Avliyakulov NK, O’Dell TJ, Martin KC (2012) Activity-dependent transport of the transcriptional coactivator CRTC1 from synapse to nucleus. Cell 150:201–221Google Scholar
- Frey S, Frey JU (2008) Chapter 7 “synaptic tagging” and “cross-tagging” and related associative reinforcement processes of functional plasticity as the cellular basis for memory formation. In: Lacaille JC, Castellucci VF, Belleville S, Sossin WS (eds) Progress in brain research. Elsevier, New York, pp 117–143Google Scholar
- Frey U, Morris RGM (1997) Synaptic tagging and long-term potentiation. Nature 385:533–536Google Scholar
- Guzowski JF, Lyford GL, Stevenson GD, Houston FP, McGaugh JL, Worley PF, Barnes CA (2000) 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. J Neurosci 20:3993–4001PubMedGoogle Scholar
- Köhrmann M, Luo M, Kaether C, DesGroseillers L, Dotti CG, Kiebler MA (1999) Microtubule-dependent recruitment of Staufen-green fluorescent protein into large RNA-containing granules and subsequent dendritic transport in living hippocampal neurons. Mol Biol Cell 10:2945–2953PubMedCrossRefPubMedCentralGoogle Scholar
- Lyford GL, Yamagata K, Kaufmann WE, Barnes CA, Sanders LK, Copeland NG, Gilbert DJ, Jenkins NA, Lanahan AA, Worley PF (1995) Arc, a growth factor and activity-regulated gene, encodes a novel cytoskeleton-associated protein that is enriched in neuronal dendrites. Neuron 14:433–445PubMedCrossRefGoogle Scholar