Chapter 11 Spine dynamics and synapse remodeling during LTP and memory processes
Introduction
A main approach to understanding learning and memory mechanisms has been to examine how information storage occurs at the level of a synaptic network. The answer to this question is now widely accepted to involve the contribution of properties of synaptic plasticity and in particular, properties such as long-term potentiation (LTP) and long-term depression (LTD; Bliss and Collingridge, 1993; Cooke and Bliss, 2006). These properties, through a lasting modification of the efficacy of synaptic transmission, are believed to durably alter the integration of synaptic responses in target neurons and consequently their probability to fire in response to a specific input. This in turn will re-shape the population of cells activated by the input, providing therefore a mechanism which, at the level of a neuronal network, fulfills the criteria expected for a learning process. Indeed, much evidence indicates that these properties of plasticity are intimately associated to learning and memory mechanisms (Cooke and Bliss, 2006). LTP and LTD are induced by patterns of activity that are physiologically relevant and enhanced during learning in regions critical for memory processes such as the hippocampus (Whitlock et al., 2006). Also many examples of pharmacological or genetic studies in rodents have shown correlations between the capacity to express these properties and the performance in behavioral learning tasks (Tang et al., 1999; Cui et al., 2004).
These results have thus strongly stimulated research on the cellular and molecular mechanisms underlying these properties of plasticity. In particular, the identification of the locus (pre- or postsynaptic) and nature of the events responsible for the lasting increase in synaptic efficacy has represented an important issue and a continuous subject of debate (Malinow and Malenka, 2002). While the answer is likely to be complex, much evidence indicates that modifications in the expression of postsynaptic glutamate receptors represent a major mechanism accounting for the changes in synaptic efficacy (Malinow and Malenka, 2002; Nicoll, 2003). Currently, the most accepted view proposes that NMDA receptor activation during high-frequency stimulation leads to a rise in calcium in dendritic spines which in turn activates signaling cascades, among which protein kinases, such as calcium/calmodulin dependent protein kinase II or protein kinase C, are likely to play important roles (Lisman et al., 2002). Through a sequence of molecular events that are not yet fully understood these signaling cascades probably affect the expression of specific subunits of AMPA receptors at the synapse and thus the sensitivity to glutamate of the postsynaptic structure (Malinow and Malenka, 2002). A main mechanism contributing to synaptic enhancement thus probably involves a rapid regulation of receptor expression at the synapse.
There are however also other mechanisms that have been reported in association with synaptic plasticity and in particular many studies have examined the possibility that the structural organization of the synapse or the number of synapses could be modified (Yuste and Bonhoeffer, 2001). Spines have indeed been shown to be dynamic structures (Matus, 2000) that can be replaced at a rather high rate in young animals and with some plasticity that remains even in the adult. The possibility that structural changes are associated with LTP or LTD remains therefore an interesting and pertinent issue. We review here some of the evidence supporting this hypothesis and discuss these results in the context of new data showing spine plasticity and turnover.
Section snippets
Morphological changes associated to synaptic plasticity
Ultrastructural analyses of spine synapses under conditions of plasticity have revealed many changes in the shape or size of spine synapses going from enlargements of the spine head, formation of protrusions, including spinules, or modifications in the convexity or concavity of spines (Lee et al., 1980; Fifkova and Anderson, 1981; Chang and Greenough, 1984; Desmond and Levy, 1986; Chang et al., 1991). However, a very frequent finding that has been associated with changes in synaptic activity or
Morphological remodeling of activated spines
Most of the morphological changes reported above under plasticity conditions were in fact observed following large-scale analyses of synapses using EM approaches. A major drawback of this type of approach is related to the impossibility to really appreciate how exactly they were related to activity, whether they concerned mainly or exclusively activated synapses and what was their evolution over time. Only a few studies developed approaches to try to address this issue. In previous work in
Synaptogenesis associated to plasticity
A second very interesting morphological correlate of LTP mechanisms is the possibility that plasticity also involves the growth of new protrusions and formation of new synapses. Work by several laboratories provided evidence for such a process in association with LTP stimulation (Engert and Bonhoeffer, 1999; Maletic-Savatic et al., 1999; Toni et al., 1999). Such changes were mainly reported under in vitro conditions, but also following sensory stimulation in the cortex of adult animals (
Mechanisms of plasticity-induced synaptogenesis
If synaptogenesis and synaptic enhancement are two separate mechanisms induced by the same patterns of activity, an important issue then is to understand how they are regulated. Experiments show that both of them require NMDA receptor activation and depend on calcium influx in the postsynaptic cell. A further link between protrusion growth and potentiation mechanisms concerns the molecular events contributing their regulation. In particular, protein kinases, such as PKC, and also CaMKII, which
Spine turnover and synapse formation mechanisms
An important new aspect of the mechanisms of spine dynamics was brought by experiments of repetitive confocal imaging in living mice. Studies by several groups provided evidence that dendritic spines do undergo some sort of turnover and that there exist a process of continuous growth and elimination of spines (Grutzendler et al., 2002; Trachtenberg et al., 2002). Although there has been some debate about the magnitude of this phenomenon, an issue that may be related to the approach used for
Memory and synapse formation mechanisms
The interesting implication of these new data is that in young cortical structures, development of synaptic contacts on a given neuron occurs through a mechanism of trial and error where most of generated protrusions are in fact rapidly eliminated. In this process a factor that seems to be important to stabilize new protrusions is the presence of an active terminal in the vicinity. The glutamate so released could drive the expression of a PSD on the new spine and thus promote its stabilization.
Conclusion
Since the discovery that LTP induction in hippocampus not only affects synaptic efficacy but also promotes growth of new protrusions, evidence has continued to accumulate indicating that spines are indeed dynamic structures that may undergo continuous replacement throughout life. Although it appears that these dynamic properties are mainly expressed in young developing cortex, a capacity for structural plasticity is clearly retained in adult animals (Grutzendler et al., 2002; Trachtenberg et
Acknowledgment
This work was supported by the Swiss Science Foundation and the European project Promemoria.
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