When scientists began to think seriously about the possible involvement of LTP in memory in the animal, a theoretical conundrum arose. If synapses can be potentiated and this potentiation is very long-lasting, over time the synapses will be driven to their maximum synaptic strength. In this condition, there is no longer synaptic plasticity and no further capacity for that synapse to participate in synaptic-plasticity-dependent processes. Worse yet, over the lifetime of an animal, synapses will by random chance experience LTP-inducing conditions (presy-naptic activity coincident with a postsynaptic action potential, for example) numerous times. If LTP is irreversible, ultimately every synapse will be maximally potentiated— obviously not a desirable condition vis-à-vis memory storage.
Consideration of this conundrum raises two implications. First, synapses that are involved in lifelong memory storage must
BOX 6—cont'd DEPOTENTIATION AND LTD
be rendered essentially aplastic. In order to have good fidelity of memory storage over the lifetime of an animal, a synapse involved in permanent memory storage must be rendered immutable to a change in synaptic strength resulting from the random occurrence of what would normally be LTP-inducing stimulation. We will return to this issue in the last chapter of the book.
But what about synapses like those in the hippocampus that are not sites of memory storage, but rather whose plasticity is part of the active processing of forming new long-term memories? In order to retain their plasticity and hence their capacity to contribute to memory formation, their potentiation must be reversible. Schaffer-collateral synapses can undergo activity-dependent reversal of LTP; a phenomenon termed depotentiation (see figure). Another activity-dependent way to decrease synaptic strength is Long-term Depression, the mirror image of LTP. LTD is a long-lasting decrease of synaptic strength below baseline. Using a logic similar to that of the first paragraph, the phenomenon of dedepression of synaptic transmission is implied, although this has not been widely studied at this point.
As a practical matter, it is often difficult to separate depotentiation from LTD experimentally. For example, a "baseline" response in hippocampal slices or in vivo likely is a mixture of basal synaptic activity and activity at previously potentiated synapses. Moreover, for the most part, the stimulation protocols used to induce depotentiation are variations of the protocols used to induce LTD. Nevertheless, mechanistic investigations have made clear that depotentiation and LTD use different mechanisms (see references 30 and 31), and thus must be considered as distinct processes.
Physiologic LTD (and depotentiation) induction protocols generally involve variations of repetitive 1-Hz stimulation (see references 30 and 32). A common protocol is to deliver 900 stimuli at 1 Hz, but there also are LTD protocols that use random small variations in frequency in the 1-Hz region, and variations that use paired-pulse stimuli delivered at 1 Hz. Synaptic depression appears to be fairly robust in vivo but is quite difficult to get in hippocampal slices from adult animals. LTD in vitro is almost always studied using slices from immature animals, or cultured immature neurons, and it is possible that LTD as it is currently studied in vitro is largely a manifestation of what is normally a developmental mechanism.
One ironic aspect of the LTP/LTD story is that both phenomena at Schaffer-collateral synapses can be blocked by NMDA receptor antagonists. This suggests that calcium influx triggers both processes, and indeed current models of LTD induction hypothesize that LTD is caused by an influx of calcium that achieves a lower level than that needed for LTP induction. This lower level of calcium is hypothesized to activate protein phos-phatases selectively, and by this mechanism lower synaptic efficacy (see Box 1).
Another very different type of LTD is cerebellar LTD. Cerebellar LTD occurs at synapses onto Purkinje neurons in the cerebellar cortex. Cerebellar LTD is a very interesting phenomenon because its behavioral role is much better understood than the hippocampal plasticity phenomena we are discussing throughout this book. Among other things, cerebellar LTD is
BOX 6—cont'd DEPOTENTIATION AND LTD
BOX 6 Depotentiation and LTD. (A) Schematic illustrating LTP, Depotentiation, LTD, dedepression, and combinations of them. (B) This figure shows LTD and depotentiation in hippocampal neurons where slices receiving baseline stimulation (control, open circles) and 1-Hz stimulation (closed circles) were recorded simultaneously. FP indicates field potential. (C) These data show regulation of distinct AMPA receptor phosphorylation sites during bidirectional synaptic plasticity. Homosynaptic LTD in CA1 is associated with dephosphorylation of GluR1 at a PKA site (ser845). Depotentiation gives dephosphorylation at a CaMKII/PKC site (ser 831). Adapted from Lee et al. (31).
involved in associative eye-blink conditioning, a cerebellum-dependent classical conditioning paradigm. Considerable progress has been made in investigating the roles and mechanisms of cerebellar LTD, and prominent investigators in this field are
Masao Ito, Richard Thompson, Mike Mauk, and David Linden. Literature searches for the work of these investigators would be a good place to start for those interested in this area, but we will return briefly to cerebellar LTD in Chapter 9.
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