From Where? Synaptic Tagging Allows the Nucleus Not to Care

Most of us now accept that the formation of long-lasting memories requires the de novo transcription of plasticity-related proteins. It is also thought that the 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 the 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.