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Fig. 5. Hypothetical scheme for the partitioning of cytoskeletal microdomains between shaft and spine in dendrites. (Left) Part of dendrite in the region of a spine synapse. The axonal component (ax.), with its swollen presynaptic (pre.) bouton containing synaptic vesicles (sv.) is outlined in gray. It forms a synapse at the tip of a dendritic spine head. Inside the spine head the junctional region is marked by the postsynaptic density (psd.), a complex of scaffolding proteins that acts as the platform for assembling functional molecules such as neurotransmitter receptors and ion channels. The cytoskeleton of the dendritic spine is composed of actin filaments (barbed lines) that are inserted into the psd. The cytoskeleton of the underlying dendrite consists predominantly of microtubules (gray rods), which in dendrites are bidirectionally oriented so that some have the plus ends distally and others the minus end distally as indicated. This distribution of cytoskeletal filaments demarcates three cytoplasmic zones, an M zone in the dendrite shaft, where microtubules predominate, an A zone in the dendritic spine, where actin filaments predominate, and a T, or transition, zone. (Right) The expanded diagram shows the relationship of these zones to the delivery of materials to the synaptic domain as suggested by current evidence. Transport vesicles (blue filled circles) carry cargoes of functional molecules, such as NMDA receptors (pale blue symbols), bound for the postsynaptic membrane. These vesicles bear both microtubule-dependent (M, kinesin and dynein) and actin-dependent (A, myosin) motor molecules. Transitory detachment of kinesin and dynein from microtubule tracks provides the opportunity for the myosin motors of transport vesicles to engage with the actin filaments of dendritic spines along which they travel to the synaptic domain. Single chevrons in the vicinity of the postsynaptic membrane represent the presence of labile actin filaments in this zone.

cally in Fig. 5 where vesicles move from microtubule to microfilament transport systems at the base of the spine. The management of this putative transition remains to be determined because a thin cortical layer of actin filaments is also present within dendrite shafts. The mechanisms responsible for delivering materials via the spine cytoplasm to sites in the postsynaptic junction have significant implications for synaptic plasticity in view of growing evidence for physical exchange of receptor molecules in the postsynaptic membrane of glutamatergic synapses (6972).

The necessity of special mechanisms for transferring materials from shaft to spine raises the question of why such a partitioning of dendrite structure should exist at all. One possibility, suggested by the results of the present study, is that this separation is a specialization for regulating anatomical plasticity. As our time-lapse recordings show, the actin and microtubule domains are associated with distinct rates of plasticity. Whereas actin in dendritic spine defines a region of rapid morphological change occurring over seconds and minutes (14, 15, 17), time-lapse imaging of MAP2 suggests that microtubules in the dendrite shaft undergo little change in periods of up to 3 h. This does not exclude that dynamic changes in dendritic microtubules may occur over longer periods. Indeed time-lapse imaging of MAP2-containing microtubule bundles in transfected epithelial cells shows that gradual alterations in the configuration of the microtubule cytoskeleton can occur over periods of several hours (33). This finding suggests that MAP2-containing neuronal microtubules may have a capacity for morphological plasticity although at a rate intrinsically slower than that of actin filament arrays, which appear constantly motile in comparable recordings (14). That gradual changes in the extent and branching of dendrites can occur has been demonstrated by repetitive imaging of dendrites in superior cervical ganglia of adult rats where substantial changes in dendritic arbors have been documented over periods of weeks and months (73, 74). However, other studies support the idea that dendritic spines are the predominant site of activity-dependent morphological plasticity in the brain in vivo (for example, refs. 17 and 7578).

Taken together these observations suggest that microdifferentiation of the dendritic cytoskeleton in mature neurons may be a cellular specialization for dividing the structural support of dendrites into two levels of stability. One of these, involving microtubules, appears to respond slowly, providing morphological stability to dendrite arbors while still allowing for long-term flexibility, whereas the other, involving motile actin filaments, allows for rapid, activity-dependent changes in synaptic structure.

We thank Thierry Doll and Jean-Francois Spetz for assistance in preparing transgenic animals.

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