Silent synapses are all-or-none. The popular model for silent synapses is insertion of postsynaptic AMPA receptors into a synapse that previously had only NMDA receptors, activating the synapse (see figure). The prior existence in the synapse of the NMDA receptor is, of course, necessary for the synapse to be capable of sensing the simultaneous presence of synaptic glutamate and membrane depolarization and to trigger the AMPA receptor insertion. The NMDA receptor is normally silent for baseline synaptic transmission because the voltage-dependence keeps the ion channel blocked by Mg2+; thus, at the outset, the entire synapse is "silent." The AMPA receptor insertion renders the synapse active at baseline synaptic transmission levels, and this is hypothesized to happen in an all-or-none fashion.

Because the postsynaptic membrane of a silent synapse is devoid of AMPA receptors, the membrane depolarization necessary to allow unblocking of the NMDA channel must be provided from some distal source. Any membrane depolarization reaching a silent synapse must be propagated from a site of depolarization elsewhere in the cell— either another synapse that has AMPA receptors or a back-propagating action


potential from the soma. Thus, activation of silent synapses is likely to be exquisitely sensitive to control of the local membrane electrical properties. In this light, it is interesting to consider that local control of membrane excitability may serve as a particularly important component in controlling the activation of silent synapses.

Given this consideration, and for many other reasons as well, it is interesting to contemplate a role for local dendritic action potentials in regulating the activation of NMDA receptors (see reference 25). Gyorgi Buzsaki's lab has found that local dendritic spikes can be generated in the dendrites of CA1 pyramidal neurons, especially during periods of rhythmic activity such as those associated with learning. These local spikes are action potentials generated in the dendrite itself, that propagate within a restricted dendritic subregion, independent of an action potential firing in the cell body. The existence of these local spikes has important implications for dendritic subregion-specific information processing in a general sense, and it is also interesting to consider a potential role for these local actions in activating silent synapses.

Conversion of silent synapses into active synapses by AMPA receptor insertion is an entirely postsynaptic phenomenon. However, there has been proposed a variation of this idea that has been referred to as a "whispering" synapse. A whispering synapse has both AMPA and NMDA receptors in it, but because of a number of hypothetical factors such as glutamate affinity differences between NMDA and AMPA receptors, kinetics of glutamate elevation in the synapse, or spatial localization of the receptors, the AMPA receptors are silent (see also Box 4). A presynaptic mechanism converts a whispering synapse to being fully active. An increase in glutamate release presynaptically, resulting in an elevation of glutamate levels in the synapse then allows the effective activation of pre-existing AMPA receptors with baseline synaptic transmission. By this mechanism, a synapse that was previously silent with respect to baseline synaptic transmission is rendered detectably active. However, this alternative mechanism requires no change in the postsynaptic compartment whatsoever.

Like the retrograde messenger hypothesis, the silent synapses hypothesis has also led to a number of important and interesting experiments that warrant attention aside from the pre-versus-post debate. Specifically, these experiments have focused new attention on the importance of considering the postsynaptic compartment in a cell-biological context. Mechanisms of receptor insertion, trafficking, and turnover that had been studied in non-neuronal cells are now beginning to get the attention they deserve in neurons as well. Like retrograde signaling, experiments arising from investigating mechanisms for activation of silent synapses have led to important "spin-off" studies that are important independent of the precipitating issue of pre-versus-post. Retrograde signaling and silent synapses represent to me excellent examples of the robustness of hypothesis testing in science— regardless of the final answer on pre-versus-post, tangible benefits have already arisen out of testing the attendant hypotheses.

So what is the bottom line? Pre or Post? My reading of the literature leads me to conclude that changes are occurring in both the presynaptic and postsynaptic compartments. Even though the wide variety of physiologic studies have been inconclusive, even to those expert in the techniques and approaches, which I am not, a variety of other kinds of experiments suggest that changes are occurring in both compartments. I will highlight two different types of approaches. First, a number of experiments using sophisticated imaging techniques have found LTP to be associated with increased vesicle recycling and increased presynaptic membrane turnover (9, 10). Also, direct biochemical measurements of the phosphorylation of proteins selectively localized to the presynaptic compartment have shown LTP-associated changes. Conceptually similar experiments looking at phosphorylation of postsynaptic proteins have found the same thing. (We will return to these experiments in chapters 6 and 7.) Thus, in my mind, the imaging and biochemistry studies have fairly clearly illustrated that sustained biochemical changes are happening in both the presy-naptic and postsynaptic cell.

This conclusion and indeed all of the pre-versus-post experiments have a very important caveat to keep in mind. In trying to reach a consensus conclusion one is making a comparison across a wide spectrum of different types of experiments and different preparations. For example, one is comparing results with cultured cells versus hippocampal slices. One is trying to compare results for different types of LTP, LTP induced using pairing versus tetanic stimulation protocols. One likely is looking at different stages of LTP in comparing results from different experimental time points. Finally, in these experiments the various investigators are using material from different developmental stages in the animal, where the neurons under study are in different stages of their differentiation pathway. These considerations are a good reason to exercise caution in interpreting the experiments at this point; indeed, these issues may be contributing greatly to the apparent incompatibility of the results obtained in different labs.

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