We have shown that excitatory synaptic function (nano-structural changes) is closely related to spine morphology (micro-structural changes) and spine dynamics (macro-structural changes) in the central nervous system. We have also highlighted that synaptic plasticity is specially high during development and modifications of activity. These two occasions are thus certainly the most
appropriate to evaluate more precisely the links between spine morphology, dynamics and function that are still unclear on numerous aspects. Indeed, these forms of plasticity have been correlated temporally (functional and micro-structural changes are early events) or mechanistically (micro and macro-structural changes directly rely on actin) but the particular role of structural changes has only been suggested (Kasai et al., 2003).
Development
Spinogenesis is high during early development and overall stability of protrusions seems to increase with age (Knott and Holtmaat, 2008).
However, spinogenesis remains poorly described principally because time interval used by dynamic studies is often either too short (minutes to hours) or too long (days to months) to observe short and long-lasting events simultaneously. Different mechanisms of spine formation have been proposed but rarely observed (Ethell and Pasquale, 2005) and their relative efficacy to produce stable spines is uncertain (Garner et al., 2006).
Stability of protrusions has been reported to increase with age but the modifications of spine dynamics occurring during development are poorly described. Moreover, spines have been
categorized into populations with different life-spans, but the structural modifications associated with spine stabilization as well as the timing and mechanisms of such changes are uncertain.
Finally, importance of the developmental context on the processes of spine formation and stabilization should be clarified. Spine morphology and stability have been shown to change with maturation of the tissue but it is unknown if spinogenesis mechanisms also vary.
Activity
Alteration of activity has been reported to induce homeostatic and/or hebbian structural changes. In vivo, dynamic of protrusions is modified after alterations of sensory experience and this suggests that synaptic activity could influence spine stabilization and elimination (Holtmaat et al., 2008). In vitro, induction of LTP or LTD have been associated with spine formation and enlargement or shrinkage and pruning respectively, reinforcing the idea that spine function, morphology and dynamics could act synergistically (De Roo et al., 2008). However, relation of structural
reorganization with functional changes is still hypothetical and these distinct plasticity mechanisms are maybe only correlated, without any causal links.
Concerning micro-structural changes, spine enlargement is reported to generally occur at spines of potentiated synapses some minutes to hours after plasticity induction but its
longer-Introduction
persistence has never been assessed (Bourne and Harris, 2007). The role played by morphological changes is also unclear: modification of spine head size could serve functional or macro-structural changes and even both sequentially.
Macro-structural changes are probably the most poorly understood activity-induced modifications. Promotion of spinogenesis or pruning by LTP or LTD respectively have been reported to occur within the hours but spine behavior over longer time-periods is unknown.
Macroscopic structural changes occur exclusively on activated dendritic segments (Maletic-Savatic et al., 1999) and the increased MSBs number (Toni et al., 1999) also suggests that they appear close to functional alterations but their relation with functional changes is purely hypothetical. Finally, are spine formation or pruning associated with hebbian modifications of activity at particular synapses or are they simply unspecific global modification of a general homeostatic response?
Objectives
As exposed above, some crucial data are missing from the literature and the aim of this work is to bring elements of answer on spine behavior during development and modified activity. This should allow to determine more precisely the hypothetic links between synaptic function and spine
dynamics.
Model of development - first article
Analysis of dendritic spines during development has two advantages. First, this period of high plasticity allows to get a reliable appreciation of spine dynamics. Second, comparison of data at different periods highlights the effects induced by maturation of the tissue.
Spine macro-changes have to be precisely quantified over adequate time-period that take into account the fact that some protrusion types are highly motile and that long time-intervals can miss fast events. Then, mechanisms of spinogenesis have to be described and their capacity to produce stable dendritic spines evaluated. In parallel, observation of functional and morphological modifications occurring after spine emergence should allow a better understanding of spine stabilization processes. Finally, the role of synaptic activity on spine stabilization must be determined.
Spinogenesis, spine stabilization and turnover are also probably under the influence of developmental cues and study of these parameters at different periods should allow to distinguish spine intrinsic properties from those more related to a specific developmental period.
Model of activity - second article
Study of dendritic spines in an in vitro model of LTP should allow to clarify the hypothetical causal links between functional and structural changes.
Follow up of spine head enlargement induced by LTP over days should allow to precise the transient or persistent nature of this morphological change and will be an important clue to precise its role for hebbian changes.
Macro-structural changes induced by LTP must also be more precisely detailed. Spine formation, stabilization or elimination processes should be correlated in a spine specific manner
Introduction! Line of research
with functional changes, i.e., distinguish events occurring at or close to potentiated synapses from others. Again, a long follow-up of these macro-structural changes overs days should allow to better estimate implications of these changes for the system.
Finally, the aim is to link functional alterations at a particular synapse with micro and macro-structural spine changes. Long-term analysis of spatial and temporal correlations between these modifications are of inestimable interest for the comprehension of network remodeling mechanisms and information storage.
Introduction! Line of research