Synapse to Nucleus Signaling during Long-Term Synaptic Plasticitya Role for the Classical Active Nuclear Import Pathway

Abstract

The requirement for transcription during long-lasting plasticity indicates that signals generated at the synapse must be transported to the nucleus. We have investigated whether the classical active nuclear import pathway mediates intracellular retrograde signal transport in Aplysia sensory neurons and rodent hippocampal neurons. We found that importins localize to distal neuronal processes, including synaptic compartments, where they are well positioned to mediate synapse to nucleus signaling. In Aplysia, stimuli known to produce long-lasting but not short-lasting facilitation triggered importin nuclear translocation. In hippocampal neurons, NMDA receptor activation but not depolarization induced importin nuclear translocation. We further showed that LTP-inducing stimuli recruited active nuclear import in hippocampal slices. Together with our finding that long-term facilitation of Aplysia sensory-motor synapses required active nuclear import, our results indicate that regulation of the active nuclear import pathway plays a critical role in transporting synaptically generated signals into the nucleus during learning-related forms of plasticity.

A circadian clock in hippocampus is regulated by interaction between oligophrenin-1 and Rev-erbα

“…To conclude, our data clearly reveal some interactions between synaptic activity and circadian oscillators and implicate oligophrenin-1 in its regulation, delineating a new means of communication between synapse and nucleus 24,36,40 . These findings are further indication 36,41 that cognitive ability is influenced by circadian rhythms, and promise to provide insight into normal plasticity and the etiology of intellectual disability.…”

“…The signals generated in synapses must therefore be transported to the nucleus, and it has been shown, in sensory neurons of mollusk Aplysia and hippocampal neurons of mice, that the classical nuclear import pathway plays a critical role in transporting synaptically generated signals into the nucleus during learning-related forms of plasticity 24 . Furthermore, a recent study showed that synaptic activity induced by NMDA activation drives oligophrenin-1 into dendritic spines 12 .…”

Importin-mediated retrograde transport of CREB2 from distal processes to the nucleus in neurons

“…We previously identified an isoform of importin ␣, ApImp-␣3, in Aplysia (9). In pull-down assays in which GST-ApCREB2 was incubated with lysates of 293T cells expressing FLAG-tagged ApImp-␣3, we detected an interaction between the 2 proteins (Fig.…”

“…A slower, more persistent mechanism of signaling to the nucleus involves the transport of soluble molecules from stimulated synapses to the nucleus (6,7). Recent studies have indicated that this type of transport may involve the active nuclear import pathway (8)(9)(10).…”

“…Importin ␤1 mediates facilitated translocation of this heterotrimeric complex across the nuclear pore. In neurons, importins may also function to carry signals from distal neuronal processes to the soma and into the nucleus (8)(9)(10)(11). This finding raises a critical question: what are the synaptically localized cargoes of importins that translocate to the nucleus to alter transcription during synaptic plasticity?…”