Trends in Neurosciences
Synaptic tagging: implications for late maintenance of hippocampal long-term potentiation
Section snippets
Early LTP and late LTP
Much progress has been made in elucidating the cellular mechanisms that underly the induction and early expression of LTP ([5]), but less is known about its maintenance. A key observation is that the extended persistence of NMDA-receptor-dependent LTP beyond about four hours is critically dependent on protein and mRNA synthesis6, 7, 8, 9, 10, 11, 12, 13, 14. LTP is, therefore, divided into an `early' form whose induction is unaffected by protein-synthesis inhibitors, and a `late' form that is
Protein trafficking and the synaptic tag hypothesis
Although the identity of the proteins responsible for stabilizing LTP has not been established, its occurrence raises the following fundamental question: given that macromolecule synthesis occurs mainly in the cell body[23], how do these proteins find their way through the dendrites to the appropriate synapses where the stabilization of early LTP is required? In general, there are considered to be four hypotheses about how the synapse specificity of late LTP could be achieved (see also 11, 24,
Variable persistence: the induction of protein-synthesis-dependent LTP during the inhibition of protein synthesis
Frey and Morris[14] conducted the following test of the synaptic tag idea. Using hippocampal slices in vitro, two independent pathways were activated with low-frequency test pulses and each tetanized once (Fig. 2F). First, pathway S1 was tetanized with a strong tetanus to induce late LTP. Thirty-five minutes later, anisomycin was added to the test chamber to shut down protein synthesis, which happened quickly9, 32. Then, 25 minutes after that, with protein synthesis arrested, pathway S2 was
The identity of the tag
What is the molecular identity of the putative synaptic tag? One possibility is a change in spine-neck diameter. If synapses displaying early LTP had wider neck diameters than synapses that had not recently been potentiated, access to the synaptic apposition zone might then be easier for the large macromolecules that we assume are responsible for stabilizing LTP. Simulation studies have revealed that although changes in spine shape are not responsible for changes of synaptic efficacy, branching
Plasticity-related proteins and the role of aminergic innervation
LTP experiments typically have a three-phase design: a low-frequency test-pulse baseline, a brief period of high-frequency stimulation (or, with intracellular recording, the pairing of pre- and postsynaptic activation) followed by a second period of test pulses. We have all got so used to this arrangement that it is easy to overlook the more likely situation, in vivo, where LTP of individual synapses is probably happening frequently. The synaptic population of an individual CA1 cell is likely
Functional implications
Our concept of synaptic tagging has been developed in hippocampal slices in vitro. Future experiments should explore whether or not the concept is applicable to the intact animal and of any relevance to memory formation and learning. Two-pathway experiments of the kind we have used[14] need to be conducted in vivo, preferably in freely-moving animals. However, an indication that synaptic tagging might occur in the intact organism has already come from experiments investigating the influence of
Concluding remarks
The synaptic tag hypothesis allows us to think about the properties of LTP in a new way. In thinking about associativity, input specificity, rapid induction and persistence, we should now recognize that persistence can be variable. The usual way of thinking about associativity is in terms of the heterosynaptic interaction of two or more inputs, over a short time scale (less than one second), mediated via the voltage dependence of the NMDA receptor[70]. The synaptic tag idea points to a
Acknowledgements
This work was supported by grants of German Bundesministerium für Bildung und Forschung and of Kultusministerium of Land Saxony-Anhalt held by UF, and an MRC Programme Grant and an HFSP Grant held by RGMM.
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