Cerebellar Longterm Depression

follower Purkinje neuron. Climbing fibers originate in brain stem nuclei and are involved in processing sensory signals, such as sending a signal to the cerebellar cortex that an eye-blink has been triggered by a puff of air on the cornea. Parallel fibers originate from cerebellar granule cells, which are a major cell type in the cerebellum. Parallel fibers carry information such as auditory signals—(e.g., information that an auditory cue has been received). Thus, via this part of the circuit a coincidence of auditory cue (parallel fibers) and air-puff (climbing fibers) can lead to a depression of parallel fiber inputs onto the Purkinje neurons. This is activity-dependent synaptic plasticity, manifest as a synaptic weakening.

How does this synaptic depression translate into a behavioral change? The Purkinje neurons are the only output neurons from the cerebellar cortex—they provide the net output of the cerebellum and are involved in modulating a wide variety of motor movements including those involved in eye movement and the eye blink. Purkinje neurons use GABA as their neurotransmitter; thus, they are inhibitory. LTD at their parallel fiber inputs leads to a net loss of inhibitory output onto motor pattern generators downstream. In the case of eye-blink conditioning, this loss of inhibition causes a net enhancement of a pre-existing connection between tone-activated neurons and follower neurons that when unmasked can trigger an eye-blink (see VIIIth nerve inputs in Panel B). This connection is normally inhibited in a feed-forward fashion by the Purkinje cell output from the cerebellar cortex and, thus, is inactive. Loss of the Purkinje cell inhibitory input allows unmasking of the connection between the tone-activated cells and the blink pattern generator cells. Thus, the tone is then able to trigger the eye-blink response on its own. The conditioned stimulus (tone) now triggers the conditioned response (eye-blink), in classical conditioning parlance.

It is important to keep in mind that this is a great oversimplification of the cellular basis of eye-blink conditioning. Nevertheless, it allows us to make several important points. First, this is a specific example of the generalization that associative learning involves the unmasking of latent circuits, ones already in existence in the CNS but that become effective in triggering behavior as a result of the plasticity of their synaptic inputs (see Box 2 and Figure 8 as well). Second, it illustrates that learning does not have to be dependent upon strengthening synapses—depressing synapses is an equally effective mechanism for memory formation. A positive or negative behavioral change can be mediated by either a positive or negative change in synaptic strength, it all simply depends on the circuit in which the neuron is imbedded.

for storing information for a few minutes to an hour or so post-training (33, 47, 48). Short-term contextual fear conditioning for example, is intact in the face of NMDA receptor blockade. Some memory trace that is not NMDA receptor-dependent LTP is keeping it there. So information is being stored somehow, and it is perfectly reasonable to hypothesize that this information is converted to an LTP trace after some period(s) of delay. This specific idea would be consistent with the delayed manifestation of molecular markers for LTP induction, such as ERK activation, that we discussed previously.

To reiterate, many studies make it clear that all relevant LTP-like phenomena are not immediately triggered by environmental stimulation during the learning phase. Many post-training infusion experiments demonstrate that signal transduction mechanisms, such as ERK activation and NMDA receptor activation, necessary for LTP induction, can be unperturbed at the time of training but still be necessary for long-term memory formation. Thus, there is some delay before the LTP-associated events are necessary for memory formation. These events are not triggered immediately by the environmental stimuli— post-training infusion effects make it clear that the environmental signals set up a memory trace that subsequently triggers LTP or a similar phenomenon.

On the other hand, this does not mean that the acute signals do not trigger LTP as well. The short-term storage/information processing mechanism that we described in Sections II.A and II.B are hypothesized to utilize E-LTP as we discussed. It's just important to keep in mind the distinction that LTP may be contributing to one type of process during learning or at early stages while it contributes to memory consolidation at later stages. Post-training inhibitor effects simply mean that another round of plasticity similar or identical to LTP must also be triggered for long-term memory to be formed.

A Model for LTP in Consolidation of Long-Term Memory

The upshot of the hypothesized role of LTP in memory consolidation is that hippocampal LTP is not a long-term memory storage mechanism—it is a memory buffer. The long-term storage of hippocampus-dependent memories occurs downsteam of the hippocampus in various regions of the cortex. In these final few paragraphs, I will present a thumbnail sketch of how LTP might participate in cortical memory consolidation. Once again, I emphasize that this is not a sophisticated or realistic model—it is an illustrative example of how LTP in the hippocampus could lead to long-term changes downstream in the cortex.

The basics of the model are based on what we have seen thus far: that LTP serves to maintain information in the hippocampus, represented as a pattern of synaptic weights, during the process of memory consolidation. The output of the potentiated circuit, manifest as a result of these altered synaptic strengths, triggers long-lasting changes in the cortex and the formation of long-term memory. The "model" will simply be an elaboration of this basic idea, but with a few more specifics added.4

4The model draws inspiration from a recent lively series of exchanges between Joe Tsien and Richard Morris. Joe Tsien has promulgated the idea of ongoing synaptic reinforcement in the hippocampus, LTP-dependent, as a contributing factor for memory consolidation (50). His idea is that ongoing NMDA receptor-dependent synaptic plasticity, over a fairly long period of time (days to weeks), is necessary for long-term memory consolidation. However, this hypothesis has met with some skepticism and rebuttal (49). As such, it remains for now in the "interesting but controversial" category. Nevertheless, synaptic activity in the hippocampus clearly is necessary for memory consolidation, based on the finding that AMPA/kainite receptor blockers infused into the hippocampus can block memory consolidation. This is consistent with the idea that activity through the altered synaptic weights (resulting from LTP) is necessary for memory consolidation at downstream target sites (51, 52). My model is more in line with the Richard Morris model than the Joe Tsien model because it does not involve any ongoing production of LTP in the hippocampus as part of the memory consolidation process.

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