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Dendritic Spines - memories are made of this?

updated 13/11/02

Dendritic spines are small "door knob" shaped extensions from the surfaces of the dendritic processes of neurons, that contain post synaptic densities (PSD).  Dendritic spines are rich in actin but tend to exclude microtubules and intermediate filaments (Kaech et al, 2001).  At the cellular level, the function of dendtritic spines appears to be to insulate signalling molecules to a particular PSD certainly the all-important Ca2+ signal is limited to the individual dendritic spines (Sabitini et al, 2001). At the organismal level there is evidence to suggest that the density of dendritic spines may reflect overall mental agility (Zito & Murthy, 2002).

Figure 1. A dendritic spine. Two distinct cytoskeletal zone are present actin is concentrated in the spine its self while microtubules are excluded and present only as bi -polar arrays within the dendritic processes.  Note that bi-polar arrays of microtubules are unusual in cells. Spines tend to be devoid of organelles (esp. mitochondria), but contain endoplasmic reticulum. The volume of the spine ranges from 0.001 - 1mm3.

Dendritic spines are known to change shape, to the extend of appearing and disappearing entirely.  It has long been hypothesised that such changes may be the basis of memory itself (Bailay & Kandel, 1993; Bailey et al, 1996; Engert & Bonhoeffer, 1999; Yuste & Bonhoeffer, 2001).  The elucidation of how these elements of memory are brought about remain one of the most exciting and important in the whole of biology!  These changes in dendritic spine shape are thought to be mediated by the actin cytoskeleton (Fifova & Morales, 1992) although these details too are far from clear (see below). 

Despite their modest size, some dendritic spines contain a specialized type of smooth endoplasmic reticulum organised as stack and referred to my some as "spine apparatus" (Gray, 1982).  Ribosomes too are found in the spines, and it is considered that this constitutes a mechanism for getting newly synthesized gene products to the PSD within dendritic spines (Steward & Worley, 2001).  Specifically a mRNA encoding Arc (activity-regulated cytoskeleton-associated protein) is localised to synapses that have been activated.  However, mRNA encoding actin is not localised at dendritic spines with the concentrated protein but it is localised in the neuronal cell body (Kaech et al, 1997). In other cell types actin mRNA is localised at for example the leading edge at the site of polymerisation (Hoock et al, 1991). The localization of actin in dendritic spines is iso-form specific, forced expression of cardiac a-actin in hippocampal neurons concentrates in bundles in the dendritic shafts (Kaech et al, 1997).

The actin cytoskeleton of Dendritic Spines
Many actin-binding proteins are known to be concentrated in spines (table 1).  Photobleach recovery data of EGFP-actin in dendtritic spines indicate that 85% of the actin in dendritic spines is dynamic, with an average cycle time of 44 seconds (
Star et al, 2002). Surprisingly, the cycle time of actin was found to be independent of the size of the spines. If this is correct then the finding suggests that the architecture of actin in the spines is atypical.  Normally, F-actin filled projections from cells (e.g. microvilli) have uniform polarity barbed ends abutting the membrane with a bundling protein gathering the filaments together.  The actin cycling time in these cells is expected to be a function of the bundle length which would normally in turn be a function of the length of the projection.  Perhaps dendritic spines contain Arp2/3 complexes forming branching networks whose regulation may not be dependent on the process length.  As spines are stimulated with for example NMDA, calcium flows into the spine (through the NMDA receptor) and this leads to the slowing of actin cycling.  This inhibition is thought to involve gelsolin as the dendritic spines of gelsolin-null mice actin cycling in stimulated spine is not slowed to the same extent (Star et al, 2002).  How calcium signalling leads to inhibition of actin cycling is not immediately obvious.  However, the actin-filament severing capping activity of gelsolin (and relatives) is regulated by calcium, pH, other actin-binding proteins and phosphoinositides (see gelsolin).  The fact that gelsolin regulates the NMDA receptor calcium channel is also likely to be part of the story (Fukukawa et al, 1997). b-catenin binds cell adhesion proteins and through a-catenin to the actin cytoskeleton.  It has been shown (Murase et al, 2002), that depolarization of neurons leads to a change in localization of b-catenin from the dendritic shaft to the spines where it binds cadherins. These effects were also found in neurons treated with tyrosine kinase inhibitors such as genistein but inhibited by inhibitors of tyrosine phosphatases (orthovanadate), indicating that the b-catenin redistribution is under the control of a tyrosine kinase pathway. The net result of this is that synaptic activity increases the strength of the synapse by increasing the homotypic cadherin dependent adhesion between the presynaptic terminal and the synapse.

Protein Function References
Actin Principle cytoskeletal component of most cells (but not neurons, where microtubules dominate). Fifova & Morales, 1992
Actinfilin A kelch containing actin-binding protein. Chen et al, 2002
Adducin Promotes spectrin-actin interactions and bundles F-actin. Matsuoka et al, 2001
a-actinin An actin filament bundling protein Wyszynski et al,1997
b-catenin Binds actin filaments to cell adhesion proteins through a-catenin Murase et al, 2002
Calponin Actin, myosin II and calmodulin binding protein Agassandian et al, 2000
Caldesmon Actin binding and myosin modulating protein Agassandian et al, 2000
CaMKIIb Calmodulin dependent protein kinase IIb Shen et al, 1998
Drebrins Actin-binding & bundling proteins  Shim & Lubec, 2002
Myosin II Contractile/motor function Fifova & Morales, 1992
Spectrin Membrane cytoskeleton constituent Fifova & Morales, 1992
Table 1. Proteins enriched in Dendritic Spines
Protein Function References
MAP1B   Sanchez et al, 1997
 Table 2. Proteins enriched in Dendritic Shafts
The dilute mutation in mice and rats ablates the myosin Va gene. Myosin V is an actin based molecular motor that moves vesciclular organelles through the cell. Ultra-structural studies in both mouse (Takagishi et al, 1996) and the dilute rat (Dekker-Ohno et al, 1996) indicate that ER is absent from the dendritic spines of Purkinje cells.  As the ER is often a source of IP3 releasable calcium, this may reduce the cells excitability.  This makes sense of a human disease “Griscelli disease” in which mutations in the human myosin V gene result in ataxia, light pigmentation and a variety of immuno-deficiencies and neurological based symptoms (Hurvitz et al, 1993).
Figure 2 Specialized regions within the dendritic spine.  The post-synaptic density is in a region distinct from that of the endocytic zone, where clathrin dependent membrane re-cycling takes place (Blanpied et al, 2002).

Agassandian, C., Plantier, M., Fattoum, A., A, R. & Der Terrosian, E. (2000) Subcellular distribution of calponin and caldesmon in rat hippocampus. Brain Res. 887, 444-449.

Bailey, C.H. & Kandel, E.R. (1993) Structural changes accompanying memory storage. Annu.Rev.Physiol. 55, 397-426.

Bailey, C.H. Bartsch, D., & Kandel, E.R. (1996) Towards a molecular definition of long-term memory storage. PNAS 93, 13445-13452.

Blanpied, T. A., Scott, D. B. & Ehlers, M. D. (2002) Dynamics and regulation of clathrin coats at specialized endocytic zones of dendrites and spines. Neuron. 36, 435-449.

Dekker-Ohno, K. (1996) Endoplasmic reticulum is missing in dendritic spines of Purkinje cells of the ataxic mutant rat., Brain Res. 714, 226-230.

Egert, F. & Bonhoeffer, T (1999) Dendritic spine changes associated with hippocampal long-term storage. Nature 399, 66-70.

Fifková, E. & Morales, M. (1992) Actin matrix of dendritic spines, synaptic plasticity, and long-term potentiation, Int.Rev.Cytol. 139, 267-307.

Furukawa, K. & al, e. (1997) The actin-severing protein gelsolin modulates calcium channel and NMDA receptor activities and vulnerability to excitotoxicity in hippocampal neurons. J.Neuroscience. 17, 8178-8186.

Gray, E.G. (1982). Trends Neuroscience 5, 5-6.

Hoock, T. C., Newcomb, P. M. & Herman, I. M. (1991) b-actin and its mRNA are localized at the plasma membrane and the regions of moving cytoplasm during the cellular response to injury, J.Cell Biol. 112, 653-664.

Hurvitz, H., Gillis, R., Klaus, S., Klar, A., Gross-Kieselstein, F. & Okon, E. (1993) A kindred with Griscelli disease: spectrum of neurological involvement., Eur. J. Pediatr. 152, 402-405.

Kaech, S., Fischer, M., Doll, T. & Matus, A. (1997) Isoform specificity in the relatinship of actin to dendritic spines.  J.Neuroscience. 17, 9565-9572.

Kaech, S., Brinkhaus, H. & Matus, A. (1999) Volatile anesthetics block actin-based motility in dendritic spines.  PNAS. 96, 10433-10437.

Kaech, S., Parmar, H., Roelandse, M., Bornmann, C. & Matus, A. (2001) Cytoskeletal microdifferentiation: A mechanism for organizing morphological plasticity in dendrites.  PNAS. 98, 7086-7092.

Matsuoka, Y., Li, X. & Bennett, V. (2001) Adducin is an in vivo substrate for protein kinase C: Phosphorylation in the MARKS-related domain inhibits activity in promoting spectrin-actin complexes and occurs in many cells, including dendritic spines of neurons. J.Cell Biol. 142, 485-497.

Matus, A., Bernhardt, R. & Hugh-Jones, T. (1981) PNAS, 78, 3010-3014.

Marase, S., Mosser, E. & Schuman, E. M. (2002) Depolarization drives b-catenin into neuronal spines promoting changes in synaptic structure and function. Neuron. 35, 91-105.

Sabitini, B.L., Maravall, M.M. & Svoboda, K. (2001) Ca2+ signalling in dendritic spines. Curr.Op.Neurobiol. 11, 349-356.

Sanchez, C., Ulloa, L., Montoro, R. J., Lopez-Barneo, J. & Avila, J. (1997) NMDA-glutamate receptors regulate phosphorylation of dendritic cytoskeletal proteins in the hippocampus.  Brain Res. 765, 141-148.

Shen, K., Teruel, M. N., Subramanian, K. & Meyer, T. (1998) CaMKIIb fundtions as an F-actin targeting module that localizes CaMKIIa/b heterooligomers to dendritic spines., Neuron. 21, 593-606.

Shim, K. S. & Lubec, G. (2002) Drebrin, a dendritic spine protein, is manifold decreased in brains of patients with Alzheimer's disease and Down syndrome. Neuroscience Lett. 324, 209-212.

Star, E. N., Kwiatkowski, D. J. & Murthy, V. N. (2002) Rapid turnover of actin in dendritic spines and its regulation by activity. Nature Neuroscience. 5, 239-246.

Stewart, O. & Worley, P. F. (2001) A cellular mechanism for targeting newly synthesized mRNAs to synaptic site on dendrites., PNAS. 98, 7062-7068.

Takagishi, Y., Oda, S., Hayasaka, S., Dekker Ohno, K., Shikata, T. & Inouye, M. (1996) The dilute-lethal (d(I)) gene attacks a Ca2+ store in the dendritic spine of Purkinje cells in mice., Neuroscience Lett. 215, 169-172.

Wyszynski, M., Lin, J., Rao, A., Nigh, E., Beggs, A. H., Craig, A. M. & Sheng, M. (1997) Competitive binding of a-actinin and calmodulin to the NMDA receptor., Nature. 385, 439-442.

Yuste, R. & Bonhoeffer, T. (2001) Morphological changes in dendritic spines associated with long-term synaptic plasticity., Annu.Rev.Neurosci. 24, 1071-1089.

Zito, K. & Murthy, V.N. (2002) Dendritic spines. Curr.Biol. 12, R5.

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