Update ArticleClustering and anchoring mechanisms of molecular constituents of postsynaptic scaffolds in dendritic spines
Introduction
Dendritic spines are the specialized structures on which the majority of excitatory glutamatergic synapses in the brain are found. Since Ramon y Cajal's first description of dendritic spines, numerous studies have shown that spine shape and density are altered by pathological and experimental influences. However, there have been no insights into the molecular constituents regulating spine function and structure.
A major cytoskeletal element in dendritic spines is actin filaments, as shown in immunoelectron microscopical studies (Matus et al., 1982, Cohen et al., 1985). Functional interaction between receptors and actin cytoskeleton was first described in 1993. Rosenmund and Westbrook (1993) reported that function of the N-methyl-d-aspartate (NMDA) subtype of glutamate receptors is regulated by the actin cytoskeleton in a calcium-dependent manner. Within the past 5 years, it has been demonstrated that spine shapes are rapidly modified in response to transmembrane signals (Hosokawa et al., 1995, Yuste and Denk, 1995, Fischer et al., 1998, Engert and Bonhoeffer, 1999, Maletic-Savatic et al., 1999). These rapid morphological changes most likely result from rearrangements of the actin cytoskeletons. In 1999, we showed that accumulation of an actin-binding protein, drebrin, within dendritic spines resulted in increased spine length, possibly via rearrangements of the actin cytoskeleton (Hayashi and Shirao, 1999). These observations indicate that many molecular components in dendritic spines interact with each other directly and indirectly, resulting in alteration of synaptic function.
Specialization of molecular components in dendritic spines results in unique postsynaptic scaffolds different from those in the dendritic shaft and cell body. Although, early in development, the molecular components that are observed in the mature spine are already expressed in the neurons, they are not accumulated in protrusions from the dendritic shaft such as dendritic filopodia or immature spines (Fig. 1A and C). The unique postsynaptic scaffolds are built up only in the mature spines (Fig. 1B and D). Thus, the characteristics of postsynaptic scaffolds in dendritic spines are now a focus of interest in studies of synaptic function.
Although diverse in size and morphology, spines contain the following general components: postsynaptic density (PSD), actin cytoskeleton and soluble regulatory proteins. PSD is a specialized structure on the intracellular side of the postsynaptic membranes of synapses in the CNS. It has been proposed that PSD is a crucial element in the organization of neurotransmitter receptors (Kennedy, 1997, Ziff, 1997, Kennedy, 1998). Actin seems to provide the only structural basis for cytoskeletal organization in dendritic spines (Matus et al., 1982, Cohen et al., 1985), as spines lack microtubules and intermediate filaments (except the large branched spines on CA3 pyramidal cells, in which microtubules are clearly visible) (Chicurel and Harris, 1992). Longitudinal actin filaments have been observed in the necks of dendritic spines, and a lattice of actin filaments has been observed in the head (Landis and Reese, 1983). There are some soluble proteins, such as calcineurin (Halpain et al., 1998), drebrin A (Shirao, 1995) and α-actinin-2 (Wyszynski et al., 1998), which are specifically concentrated within spines. It has been suggested that some soluble proteins are kept in place by protein–protein interaction with the actin cytoskeleton, and that these proteins play regulatory roles in the function of neurotransmitter receptors (Rosenmund and Westbrook, 1993) and in spine morphology (Hayashi et al., 1996, Hayashi and Shirao, 1999).
What kind of mechanism is responsible for the specialization of molecular constituents at postsynaptic scaffolds within dendritic spines? This article focuses on recent advances in the understanding of the clustering and anchoring mechanisms of NMDA receptors and actin filaments, and involvement of actin-binding proteins, in dendritic spines.
Section snippets
Clustering and anchoring of NMDA receptors within dendritic spines
In cultured neurons, NMDA receptors are clustered in the dendritic shafts and in cell bodies, early in development, but the number of NMDA receptor clusters increases later in development, and most of them are anchored within dendritic spines (Rao and Craig, 1997). The NMDA receptors are complexes of NR1 and NR2A-D subunits. NR2A-D subunits have distinct expression profiles that are regulated developmentally (Monyer et al., 1994, Okabe et al., 1998). Chronic treatment with an NMDA receptor
Anchoring of actin filaments
Although actin is a major cytoskeletal element of dendritic spines, the mechanism by which actin filaments are anchored in the spines remains unclear. A mechanism for enrichment of actin within a subcellular compartment was suggested in 1993. Hill and Gunning (1993) showed that the 3′-untranslated sequences of actin guided the sorting of actin isoform mRNAs in non-neuronal cells. The transport of actin mRNA may provide a mechanism for enrichment of actin within a subcellular compartment via
Characteristics of actin filaments in dendritic spines
Drebrin is an F-actin-binding protein (for review, see Shirao, 1995) which has ADF-H domain in its N-terminal region (Lappalainen et al., 1998). Drebrin A is a neuron-specific isoform. Drebrin E is a ubiquitous isoform (Shirao and Obata, 1986, Keon et al., 2000). Drebrin competitively inhibits the actin-binding activity of tropomyosin, fascin and α-actinin (Ishikawa et al., 1994, Sasaki et al., 1996), and imparts a unique character to the actin cytoskeleton bound to it (Shirao, 1995).
Activity-dependent anchoring of actin filaments in dendritic spines
Recent developments in the study of dendritic spine cytoskeleton support the idea that rapid reorganization of actin cytoskeleton is the basis for rapid morphological change of dendritic spines in response to synaptic activity (Engert and Bonhoeffer, 1999, Maletic-Savatic et al., 1999). Although NMDA receptor activation results in an increase of intracellular calcium, it is not yet known whether this increased calcium actually induces reorganization of actin cytoskeleton in dendritic spines.
It
Conclusion
Recent technological progress (e.g. cDNA cloning, expression studies of tagged proteins, and immunofluorescence analysis using confocal microscopy) has yielded great amounts of information about unique molecular constituents of dendritic spines. Over 100 years after Ramon y Cajal's first description of these spines, we can now monitor dynamic changes in spine morphology in relation to synaptic activity and synaptic plasticity. We can even trace translocations of specific proteins in living
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