, 2002, Majewska et al., 2000a and Sabatini et al., 2002). Calcium compartmentalization by spines could allow long-term synaptic plasticity at individual synaptic sites (Holmes,

1990, Koch and Zador, 1993 and Malenka et al., 1988). Indeed, very high spine calcium accumulations are triggered by stimulation protocols that generate LTP (Koester and Sakmann, 1998 and Yuste et al., 1999). Moreover, the increase in synaptic strength after LTP is accompanied by a corresponding increase in the volume of the spine head (Matsuzaki et al., 2004), and selleck chemicals llc this volume is proportional to the size of the PSD and the number of glutamate receptors in it (Arellano et al., 2007a, Harris et al., 1992 and Schikorski and Stevens, 1999). All of these separate pieces of evidence are consistent with a model by which the stimulation of an individual spine, when paired with backpropagating action potentials, triggers a calcium influx specific to the activated spine and elicits LTP by inserting glutamate receptors into that synapse, without affecting the neighboring synapses. Besides this

biochemical compartmentalization, there is an additional mechanism by which spines could enable input-specific alterations in synaptic strength. If the spine neck has a significant resistance, as discussed above, changes in its length or width, or in its electrical properties that may not be morphologically detectable, could alter synaptic strength. This idea, first

proposed by Rall (Rall, 1974a and Rall, Metformin 1995), has become more tenable through the realization that spines are not rigid structures but can dynamically alter their shape and length, in a matter of seconds (Dunaevsky et al., 1999 and Fischer et al., 1998). In fact, significant alterations in the dimensions of the spine neck occur spontaneously (Dunaevsky et al., 1999, Majewska et al., 2000b and Parnass et al., 2000) and changes in spine neck diffusion occurs in response to synaptic activity (Bloodgood and Sabatini, 2005). Moreover, electron microscopic reconstructions indicate that the spine neck becomes shorter whatever and wider after LTP (Fifková and Anderson, 1981 and Fifková and Van Harreveld, 1977), potentially explaining the increase of synaptic strength. These neck-based changes in synaptic strength could be fast and would not require altering the number of synaptic receptors, but merely alter the spine’s electrical coupling to the dendrite. Finally, there is a third mechanism by which spines provide enhanced synaptic plasticity. As mentioned above, by specifically enabling connections with a larger variety of axons, spines could allow rewiring that would be much more extensive than if synapses were on dendritic shafts and were to contact only a limited assortment of axons (Chklovskii et al., 2002).