Conclusion And Future Directions

The aim of this chapter was to provide a synopsis of the present knowledge and concepts of synapse-to-nucleus-and-back signaling mechanisms. Despite the progress in recent years a consistent theoretical framework for the role of activity-driven gene expression in the induction and maintenance of synaptic plasticity is still lacking. A unifying hypothesis of synapto-nuclear signaling will have to solve many problems that are currently not convincingly addressed. The view that molecules are transported from single synapses to the nucleus in response to synaptic activity is largely based on evidence observed in Aplysia motor neurons but has not been convincingly shown in vertebrate neurons like the pyramidal cells of the cortex and hippocampus. Moreover, it needs to be addressed whether dendritic transport of signaling molecules is fast enough to account for the rapid induction of plasticity-related gene expression. An integrated view of synapse-to-nucleus communication will also have to deal with the problem of input specificity. It has been convincingly shown that the spatial and temporal diversity of neuronal Ca2+ transients has important consequences for gene transcription. Thus, activity-dependent gene expression depends on the Ca2+ entry site, the amplitude and the temporal dynamics of the Ca2+ signal, and the subcellular compartment it invades. Furthermore, the Ca2+-binding proteins sensing these Ca2+ signals and triggering the target interactions upon Ca2+ binding will most likely not only include CaM and Calcineurin. The identification of other neuronal calcium sensor proteins involved in synapse-to-nucleus communication might therefore provide even more specificity for the transduction of Ca2+ signals to the nucleus. Next, it will be important to elucidate how activity-driven gene expression feeds back to the activated synapses. Part of this problem is to understand why the expression of activity-regulated genes is necessary for a synapse to undergo long-term structural changes. Thus, it will be important to understand the molecular mechanisms by which the presence of activity-regulated genes render a potentiated synapse specific as compared to other synaptic input, and whether the expression of plasticity-related genes is instructive to induce certain forms of synaptic plasticity even in the absence of enhanced synaptic activity. Answers to these questions will probably help to learn more why neurons invented synapse-to-nucleus communication and activity-driven gene expression despite the possibility of local protein synthesis from dendritic mRNAs. A possible answer might be that dendritic spine synapses need a nuclear feedback mechanism to adjust synaptic weights during processes generally referred to as synaptic scaling. Synapto-nuclear signaling could be a mechanism to provide the neuron with proteins needed for input specificity by destabilizing less efficient synapses (i.e., proteins like SNK and Homer1a) and contributing protein components that transform pre-existing synaptic macromolecular complexes into less plastic structures, i.e., the mushroom-shaped mature spine that survives potentially for many years or even the lifespan.*

'The work of M.R.K. is supported by the BMBF, DAAD, DFG, the Land Sachsen-Anhalt, and the Schram Foundation.

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