The answer is that the recovered depotentiation of a recently silenced synapse, unlike normal depotentiation, is actually NMDA dependent, and not mGluR dependent. In addition, the other thing to recall is that if you depotentiate, it does not recover its NMDA dependence even after an hour. However, if you depotentiate an active synapse and we know that this depotentiation is mGluR dependent, it immediately switches back to being an NMDA dependent in terms of any further depression. So basically, we know that any time you can return to this active state, that any depression out of that active state is an NMDA dependent. From those two pieces of data we conclude that the vector from recently silent actually goes to active. We have these different states of the synapse: silent, depressed, active, potentiated, and their interrelationships.

Our working model is that active synapses have both NMDA and AMPA receptors, and they can potentiate, where they insert AMPA receptors into the membrane. The depotentiation from that state is now mGluR dependent, even though depression from this state is totally NMDA dependent. It raises an interesting possibility that you may be inserting not only AMPA receptors in this case, but also metabotropic glutamate receptors. Silent synapses have no AMPA receptors in their membrane, and when they are potentiated they receive AMPA receptors, but then they transition back into this active state. They are protected from any kind of depression for the first half an hour of their new life.

It is important because we know now that we can transition from this active state back to the silent state, which means you can potentially regenerate the silent synapses during the normal activity that the brain undergoes during both frequency activation or during forgetting. This sort of reloads the brain to store new memories, which can then be initially protected when new information comes in and causes a high-frequency activation of the inputs. We also know that the NMDA receptors are also regulated, which produces a kind of metaplasticity of the whole system.

The main conclusion that we have from this research is that both active and silent synapses can potentiate and that long-term potentiation can be graded in a single synapse. So all synapses are basically capable of storing memory traces; but silent synapses do it a little bit better. The synapses can exist in different states of plasticity and how they behave depends on what state they are coming from. The synapses move between these states in an activity-dependent manner, and the history of the synapse actually matters for plasticity, and therefore should matter for the way that memory traces are formed.

In closing I want to give credit where credit is due. Much of this research emerged from my laboratory and Johanna Montgomery played a prominent role in the study.



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