A novel signaling system from the synapse to the nucleus

One of the central unsolved riddles in neurobiological research is the identification of the activity-dependent signaling system that communicates between the synapse and nucleus. How might a synaptic event signal the gene regulatory process? More than 20 years ago Schmitt et al.[1xSchmitt, F.O. et al. Science. 1976; 1973: 114–120CrossrefSee all References[1]in a seminal review suggested that a retrograde signal, unspecified at that time, might serve this purpose. Until recently, the nature or identification of this signal has not been forthcoming.Imagine our surprise when we found that the nuclear factor-kB (NF-kB) was present within the crude synaptosome preparations taken from hippocampus[2xMeberg, P.J. et al. Mol. Brain Res. 1996; 38: 179–190Crossref | PubMed | Scopus (166)See all References[2]. Because this might represent contamination from another subcellular compartment, we searched the literature and were reassured to find that NF-kB was present in cortical synaptosomes[3xKaltschmidt, C. et al. Mol. Cell Biol. 1994; 14: 3981–3992Crossref | PubMedSee all References[3]. Because these authors had not done so, we thought it important to propose an explicit model of how this synapse-to-nucleus signaling might occur. In this model, which was in Fig. 9 of our report, it was suggested that NF-kB would be present in presynaptic terminals, postsynaptic zones, and in perinuclear cytoplasm. It would then be translocated to the nucleus from any of these sites, acting as a signal to communicate events at the synapse to the nucleus and, at the same time, regulate gene transcription. There was good evidence that the translocation of the transcriptionfactor from the distant site involved a release from an inhibitory factor triggered by protein kinase activation. Thus, we saw the possibility that kinase activation could, in parallel, regulate short-term events by phosphorylating synaptic proteins involved with neurotransmission[4xBenowitz, L. and Routtenberg, A. Trends Neurosci. 1997; 20: 84–91Abstract | Full Text | Full Text PDF | PubMed | Scopus (862)See all References[4]and long-term events by releasing one or more transcription factors to the nucleus.Imagine our initial satisfaction when a similar idea, presented in a figure in a recent review of NF-kB appeared[5xO'Neill, L.A.J. and Kaltschmidt, C. Trends Neurosci. 1997; 20: 252–258Abstract | Full Text | Full Text PDF | PubMed | Scopus (725)See all References[5]. But we were disheartened by the absence of attribution, even though the authors referred to our paper in the context of that figure. In a recent review[4xBenowitz, L. and Routtenberg, A. Trends Neurosci. 1997; 20: 84–91Abstract | Full Text | Full Text PDF | PubMed | Scopus (862)See all References[4], a figure modified from another author was included and attribution to that figure and its modification was noted in the figure caption, an approach that would have been appropriate in Ref. [5xO'Neill, L.A.J. and Kaltschmidt, C. Trends Neurosci. 1997; 20: 252–258Abstract | Full Text | Full Text PDF | PubMed | Scopus (725)See all References[5].The discovery of NF-kB in the synapses of cerebral cortex[3xKaltschmidt, C. et al. Mol. Cell Biol. 1994; 14: 3981–3992Crossref | PubMedSee all References[3]and hippocampus[2xMeberg, P.J. et al. Mol. Brain Res. 1996; 38: 179–190Crossref | PubMed | Scopus (166)See all References[2]represents a potentially important and novel mechanism for synapse-to-nuclear signaling. It will be necessary to tag these molecules to demonstrate whether, in fact, such traffic does exist. Then perhaps hypothetical figures will be replaced with laser confocal time-lapse micrography.