It can be estimated that about 30-350 genes expressed in neurons show some type of activity-dependent regulation. Of those, several belong to immediate early genes and only a subset of them like SNK42, Narp43,44, Arc45, CPG1546, or Homer-1a47, seem to have a direct role in synaptic function. These functions can, however, be quite opposite. Whereas Narp induces synaptic clustering of AMPA-receptors43,44 and increases synaptic efficacy, and CPG15 promotes synaptic maturation46, SNK42 and Homer-1a47 destabilize and reduce the number of synaptic contacts. Other immediate early genes encode transcription factors like c-Fos that control the transcription of other genes and thereby provide an activity-dependent control mechanism for the production of proteins that might also have a specific role in synaptic signaling. Finally, increased transcription levels after synaptic stimulation have been reported for a number of genes like BDNF that might have direct effects on processes of synaptic plasticity (for review see ref. 45). BDNF signaling at glutamate synapses enhances the translation of newly transported Arc and locally stored (i.e., a-CaMKII) mRNA in dendrites. Thus, the emerging picture is rather complex and no clear-cut functional scheme for activity-driven gene expression can be deduced from the present data for synaptic plasticity.
This might change with a more elaborate picture that takes into account that different protocols to induce synaptic activity might also lead to different patterns of synaptic plasticity-related gene expression. A major obstacle for many years has been to decipher the molecular pathways that induce activity-dependent neuronal gene transcription and we are just at the beginning to understand these molecular mechanisms (see also above). Apart from the putative consequences of activity-dependent gene transcription for synaptic input there are, however, also a number of other intriguing questions that have not been addressed yet in much detail. These concern the putative cellular targets for de novo transcribed or upregulated gene products. It is thought that newly synthesized mRNAs or proteins are targeted specifically to activated synapses by means of a synaptic tag48. The 'tagging' hypothesis proposes that potentiated synapses are able to capture newly synthesized proteins by not yet clearly defined mechanisms. Synaptic tagging could explain how local events at the synapse might provide the basis for the realization of plastic events at individual synapses via such a capturing mechanism without the necessity for synapse-to-nucleus communication. This concept is particularly attractive because it is at present still essentially unclear whether a privileged connection between a single synapse undergoing plastic events and the nuclear gene transcription that is induced by synaptic activity exists and whether this is at all possible. A number of studies argue against this possibility and foster the idea that synaptic plasticity-related signaling to the nucleus can be achieved without direct transport of molecules from individual activated synapses. One of the strongest arguments against a role of synapse-to-nucleus signaling in establishing long-lasting plastic events at the synapse comes from studies of Dudek and co-workers who could show that the conversion of early-phase LTP to late-phase LTP can be induced by antidromic stimulation of CA1 neurons in the absence of excitatory synaptic activity49. Moreover, in the same study it was found that somatic action potentials are sufficient for the phosphorylation of ERK and CREB. In contrast, however, Deisseroth et al.4 reported that synaptic stimuli but not electrically induced action potentials are a prerequisite for the phosphorylation of CREB. Further arguments against the necessity of synapse-to-nucleus communication for the maintenance of long-term synaptic plasticity were introduced in a recent review from Adams and Dudek50. The authors state that the amount of protein needed in the nucleus to be relevant for gene transcription is relatively high as compared to conceivable protein concentrations in single dendritic spines. Moreover, the translocation to the nucleus would dilute this concentration at least 2000-fold with respect to the much larger nuclear volume. It should be taken into account, however, that signaling molecules for synapse-to-nucleus communication are efficiently targeted to active sites of gene transcription of plasticity-relevant genes. A more stringent point is raised by the finding that some plasticity-relevant genes like Arc can be induced as early as 2 min following sustained neuronal activation via electroconvulsive shock51. This rapid nuclear response seems to be too fast for a synapse-to-nucleus transport process. But it should be emphasized that electroconvulsive shock does not reflect the in vivo situation of synaptic transmission even under pathophysiological conditions and that motor proteins like dynein exist which could transport signaling molecules within a few minutes from dendritic compartments to the nucleus. Thus, in light of the conflicting evidence provided so far it is still a matter of debate whether synapse-to-nucleus signaling is a prerequisite for the regulation of plasticity-related gene expression.
Was this article helpful?