• actin;
  • dendritic spine;
  • microtubules;
  • synaptic plasticity


  1. Top of page
  2. Abstract
  3. Cytoskeletal structures in dendritic spines
  4. Role of actin filaments in dendritic spine formation
  5. Dendritic spine abnormalities in neuropsychiatric, neurodevelopmental, and neurodegenerative pathologies
  6. Future implications
  7. Acknowledgements
  8. References

Dendritic spines are small protrusions emerging from their parent dendrites, and their morphological changes are involved in synaptic plasticity. These tiny structures are composed of thousands of different proteins belonging to several subfamilies such as membrane receptors, scaffold proteins, signal transduction proteins, and cytoskeletal proteins. Actin filaments in dendritic spines consist of double helix of actin protomers decorated with drebrin and ADF/cofilin, and the balance of the two is closely related to the actin dynamics, which may govern morphological and functional synaptic plasticity. During development, the accumulation of drebrin-binding type actin filaments is one of the initial events occurring at the nascent excitatory postsynaptic site, and plays a pivotal role in spine formation as well as small GTPases. It has been recently reported that microtubules transiently appear in dendritic spines in correlation with synaptic activity. Interestingly, it is suggested that microtubule dynamics might couple with actin dynamics. In this review, we will summarize the contribution of both actin filaments and microtubules to the formation and regulation of dendritic spines, and further discuss the role of cytoskeletal deregulation in neurological disorders.

Abbreviations used

Alzheimer's disease


autism spectrum disorders


drebrin-binding actin


long-term potentiation


microtubule-associated proteins

Dendritic spines are small protrusions emerging from their parent dendrites, and contain postsynaptic structures such as postsynaptic density and actin filaments and, under certain circumstances, microtubules. Dendritic spines observed in fixed brain tissue and cultured neurons show various shapes (Fig. 1a–c) and are generally classified into three types: the thin type having a slender neck and a small head, the mushroom type having a short neck and a relatively large head, and the stubby type having no neck. All these categories reflect a continuum rather than separate classes (Rochefort and Konnerth 2012). And in living neurons, spine shapes easily interchange among the above three types. In other words, spine morphologies are snapshots of dynamic morphological changes. In fact, dendritic spines dynamically change their morphology in response to synaptic transmission, which happens to be the structural basis of synaptic plasticity.


Figure 1. (a) DiI labeling of a 21-day-in vitro hippocampal neuron. (b) Enlarged images of the areas indicated by the square in (a). (c) Golgi staining image of hippocampal neuron of the adult rat brain. (d) Triple staining images of a 21-day-in vitro hippocampal neuron. Red shows actin filament stained with phalloidin. Green shows drebrin immunostained with anti-drebrin antibody (M2F6). Blue shows microtubule-associated proteins immunostained with anti-MAPs anti-serum. Note that yellow signals indicate co-localization of drebrin and F-actin in dendritic spines. (e) Schematic presentation of actin filaments, microtubules and postsynaptic density (PSD). Scale bars are 20 μm in (a) and 2 μm in (b).

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Although at early developmental stages neurons form many thin filopodia on their dendrites (Fig. 2a and b), they are just similar to those emerging from non-neuronal cells and do not show any morphological plasticity. Only mature neurons have dendritic spines capable of morphological plasticity depending on synaptic activity (Fig. 2e and f). How does a neuron form dendritic spines? When a presynaptic terminal comes into contact with a filopodium, a cluster of actin filaments appears at the contact site in the filopodium (Fig. 2c and d). Eventually, the cluster-containing processes change into mature dendritic spines (Takahashi et al. 2003). In this mini-review, we will delineate the basic cytoskeletal elements in dendritic spines and discuss the role of cytoskeletons in the dendritic spine formation, synaptic plasticity, and neurological disorders.


Figure 2. Schematic representation of dendritic spine formation from dendritic filopodia. (a) and (b) are filopodia. A filopodium at early developmental stages of a neuron is similar to that emerging from a non-neuronal cell. When a presynaptic terminal contacts a filopodium, drebrin is accumulated at nascent contact sites in (b), (c) and (d) are immature spines. Drebrin-binding actin filaments form stable actin pool at postsynaptic site in (c). Once drebrin-binding actin (DB-actin) filament clusters are formed, postsynaptic density (PSD)-95 and glutamate receptors are accumulated into these clusters in (d). (e) and (f) are mature spines. When DB-actin filament is predominant in the spine, the spine morphology is stable. Long-term potentiation (LTP) signals might form mushroom-type spines in (e). When ADF/cofilin-binding-actin filaments predominate, the spine morphology is unstable in (f).

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Cytoskeletal structures in dendritic spines

  1. Top of page
  2. Abstract
  3. Cytoskeletal structures in dendritic spines
  4. Role of actin filaments in dendritic spine formation
  5. Dendritic spine abnormalities in neuropsychiatric, neurodevelopmental, and neurodegenerative pathologies
  6. Future implications
  7. Acknowledgements
  8. References

Overview of actin filaments

An actin filament consists of double helix of actin protomers decorated with its binding proteins. The physical and biochemical properties of actin filaments are varied among different cell types and even among subcellular regions. This is not because actin molecule isoforms are different, but because filament-binding proteins, such as tropomyosin and drebrin, are so (Shirao et al. 1992; Sekino et al. 2007) and actin depolymerizing factor (ADF)/cofilin (Bamburg et al. 1999).

In addition, an actin filament has a polarity. It has a barbed end and a pointed end, which are named after the electron microscopic image of actin filaments decorated with heavy mero-myosin as a metaphor for the arrowhead (Huxley 1963; Ishikawa et al. 1969). It is known that actin filaments keep treadmilling reaction (Wegner 1976) when their ends are not capped by actin-capping proteins. According to the treadmilling reaction, actin protomers are continuously added (polymerized) at the barbed end and removed (depolymerized) at the pointed end (Pollard and Mooseker 1981). Protrusive motility of a cell generally proceeds by a treadmilling reaction in cooperation with actin-binding proteins (Achard et al. 2010), such as ADF/cofilin, actin-related proteins Arp2 and Arp3 (Arp2/3) complex (Pollard and Beltzner 2002), and WASP/Scar family (Symons et al. 1996), when the filaments show isotropic orientation. Fluorescent recovery after photobleaching revealed the rapid turnover of actin in dendritic spines (Star et al. 2002). This suggests that the treadmilling reaction of actin filament occurs in dendritic spines. However, because a single-molecule imaging assay indicates that F-actin in dendritic spines is made mostly of short filaments and is not well aligned (Tatavarty et al. 2009), the treadmilling reaction might not generate the driving force that changes spine morphology.

In vitro studies have demonstrated that the total amount of actin filaments is regulated by the amount of monomeric actin and ATP concentration (Korn et al. 1987), while the polymerization speed and the final length of actin filaments are regulated by the number of seeds for polymerization (the initial number of free ends of the actin filaments). In vivo, however, the content of actin filaments is much lower than what has been deduced from the in vitro study. Although the mechanism is not yet fully elucidated, various kinds of actin-binding proteins are thought to play important roles in regulating the content of actin filaments in vivo. When cultured neurons are treated by latrunculin A, which sequestrates actin monomers, actin filaments disappear. Thus, a possible regulatory mechanism of biased actin filament distribution within a cell is a local sequestration of actin monomers by actin sequestering proteins such as β-thymosin and ADF/cofilin (Pollard and Borisy 2003). Another possible mechanism is the capping of the barbed end of an actin filament, which results in the inhibition of actin polymerization at the barbed end. Relative facilitation of actin depolymerization at the pointed end consequently decreases the content of actin filaments. Interestingly, ADF/cofilin is known to facilitate the actin depolymerization by increasing the rate of dissociation from the pointed end of actin filaments as well as sequestering actin monomers (Carlier et al. 1997). Because its actin-binding activity is modulated by phosphorylation, the phosphorylation signals might cause the locally biased actin-filament depolymerizing activity of ADF/cofilin.

Actin filaments can form various kinds of higher order structures. In cooperation with actin-bundling proteins, such as α-actinin and fascin, they form a straight bundle. α-actinin-mediated actin bundle is a straight long bundle, typically linking adhesion plaques within a cell. Fascin forms a thin actin bundle consisting of five to six filaments, a typical actin structure found in a filopodium of axonal growth cone (Sasaki et al. 1996). On the other hand, filamin forms a meshwork of actin filaments (Nakamura et al. 2011).

Unique character of actin filaments in dendritic spines

Actin filaments are remarkably highly accumulated in a dendritic spine (head) compared with the parent dendrite (Fig. 1d and e). Although the accumulation mechanism has yet to be elucidated, it is known that actin filaments in dendritic spines have a unique character because of a high drebrin content (Sekino et al. 2007).

Variations in the helical structure of actin filaments can be modulated by the binding of actin-binding proteins (Sharma et al. 2012). The pitch of an actin filament plays an important role in modifying the relationship (binding activity) between actin filaments and actin-regulating proteins. A typical side-binding protein of actin filament, tropomyosin, forms a helix pitch of 36.5 nm, which is similar to the pitch of bared double helix of actin protomers. In contrast, drebrin forms the 40.0 nm pitch of actin filaments (Sharma et al. 2011). The difference in the structural and dynamic states of actin filaments is thought to influence their response to other actin-regulating proteins. While tropomyosin-binding actin filaments are biochemically registant against gelsolin, a severing protein of actin filaments, drebrin-binding actin (DB-actin) filaments are labile against gelsolin (Ishikawa et al. 1994). Similarly, while an actin depolymerizing reagent, cytochalasin D, induces the depolymerization of actin filaments in neuronal cell bodies and dendritic shafts, it paradoxically induces the increase in DB-actin filaments in dendritic spines (Takahashi et al. 2009).

The difference of actin filament character also affects the higher structures composed of actin filaments, such as bundle formation and network formation. DB-actin filaments form thicker winding bundles and sometimes circling bundles, while tropomyosin-binding actin filaments form straight bundles within a cell, called stress fibers, in cooperation with α-actinin. Replacing tropomyosin with drebrin through the cDNA transfection technique resulted in stress fibers changing into thick winding actin bundles (Shirao et al. 1994). Thus, it can be concluded that the cell forms many protrusions, some of which sometimes become much longer than the cell length (Shirao et al. 1992).

A dendritic spine contains two distinct pools of F-actin. The dynamic pool of actin filaments is located at the tip of the spine, whereas the stable pool is located in the core of the spine (Honkura et al. 2008). Interestingly, DB-actin filaments are located in the core of spines (Aoki et al. 2005); they are also capable of forming higher order complexes (Grintsevich et al. 2010). It is therefore suggested that DB-actin filaments compose the stable pool of actin filaments in the dendritic spine core.

Overview of microtubule

Microtubules are polarized heteropolymers composed of α- and β-tubulin subunits, which are oriented in a head-to-tail arrangement, with β subunit projecting to the fast-growing end. Tubulin subunits polymerize in the presence of GTP (Vallee 1986). Microtubules display two functionally different ends. While the slow growing end, termed the minus end, is attached to the microtubule organizing center, the fast-growing end, termed the plus end, projects to the cell periphery. The dynamic behavior of microtubules is characterized by the growing and shrinking of the plus end in a process termed dynamic instability (Mitchison and Kirschner 1984). Thus microtubules can polymerize and depolymerize according to cell requirements. The half-life of microtubules is also contributed by several molecular mechanisms that include the binding of microtubule-associated protein (MAPs, TIPs), the post-translational modification in tubulin and the difference of tubulin isotypes (Conde and Cáceres 2009; Janke and Bulinski 2011).

Microtubules in dendritic spines

The presence of microtubules and their associated proteins in dendritic spines has been controversial. Electron microscopic studies conducted in the early 1980s suggest that microtubules are capable of penetrating dendritic spines (Westrum et al. 1980; Gray et al. 1982). However, technical caveats led to the assumption that dendritic spines were devoid of microtubules (Fiala et al. 2003). In the last 5 years, several studies have drawn the attention of neurobiologists to a possible role of microtubules in dendritic spines. Using fluorescence-tagged proteins coupled with live 3D imaging, Gu et al. (2008) showed the presence of microtubules in dendritic spines. Microtubules are mainly found in mushroom-type dendritic spines (Fig. 1e).

The presence of microtubules in dendritic spines is correlated with synaptic activity. Brain-derived neurotrophic factor (BDNF) increases the entry of microtubules into dendritic spines. Nocodazole inhibits BDNF-induced dendritic spine formation by impairing microtubule polymerization. In contrast, a small concentration of taxol, which enhances microtubule polymerization, increases BDNF-induced dendritic spine formation, indicating that microtubule (MT) dynamics is regulated by either eliciting the formation of new dendritic spines or inhibiting the disassembly of previously formed spines (Gu et al. 2008). The fact that microtubules are found in dendritic spines in an activity-dependent manner suggests that this is not a stochastic process (Hu et al. 2008). Microtubules that penetrate dendritic spines are highly dynamic and are decorated at their plus end with the MT plus end tracking protein +TIP protein, EB3 (Hu et al. 2008; Jaworski et al. 2009). In contrast, microtubules at the dendritic shaft are more stable (Kaech et al. 2001; Jaworski et al. 2009). Interestingly, inactivation of EB3 using shRNA reduces dendritic spine formation (Gu et al. 2008; Jaworski et al. 2009).

Coupling of microtubule dynamics to actin filament dynamics

The presence of microtubules containing EB3 at dendritic spines regulates the assembly of actin filaments, as suggested by experiments using jasplakinolide treatments to reverse EB3-inactivation (Jaworski et al. 2009). The presence of +TIP proteins decorating dynamic microtubules may have profound implications for the capture process of microtubules, coupling MT dynamics with actin polymerization. The binding activity of EB3 to drebrin may contribute to the interaction between microtubule and actin filaments (Geraldo et al. 2008). Coupling microtubule and actin filament dynamics might be essential for temporal and local regulation of dendritic spines. In this context, other proteins could mediate such a coupling as well as EB3.

IQ motif containing GTPase activating protein (IQGAP), a scaffold protein highly expressed in neurons, may coordinate the dynamics of both microtubules and actin filaments (Jausoro et al. 2012). IQGAP can interact not only with Rac and Cdc42 (Kuroda et al. 1996) but also with cytoplasmic linker protein 170 (Fukata et al. 2002) and EB1 (Watanabe et al. 2009). Recently, it has been shown that IQGAP1 promotes both dendrite development (Swiech et al. 2011) and dendritic spine formation (Gao et al. 2011). Moreover, IQGAP1 also plays a role in synaptic plasticity and memory formation (Schrick et al. 2007; Gao et al. 2011). As IQGAP can interact with +TIPs proteins in microtubules, it is possible that dynamic microtubules penetrating dendritic spines are necessary to promote IQGAP functions. Interestingly, it has been shown that an IQGAP mutant lacking its C-terminal domain, the domain involved in CLIP170 binding, does not decrease the number of dendritic spines in cultured neurons, but decreases the proportion of mushroom-type spines (Jausoro et al. 2013).

Stable and dynamic microtubules

The presence of two populations of stable and dynamic microtubules at dendrites may reflect some specialization for microtubules penetrating dendritic spines. MAP2 is a potent microtubule stabilizing factor that promotes the formation of dense and stable microtubule bundles (Takemura et al. 1992). Microtubules at dendritic spines seem dynamic as live imaging experiments using MAP2-GFP failed to identify microtubules at dendritic spines (Kaech et al. 2001). Among neuronal MAPs, MAP1B does not stimulate microtubule bundling, being a good candidate for maintaining a population of more dynamic microtubules (Black et al. 1994; González-Billault and Avila 2000; González-Billault et al. 2001). Thus, under some conditions, microtubules present at dendritic spines are likely to contain MAP1B (Tortosa et al. 2011).

Neurons lacking MAP1B show a robust decrease in mushroom-type spines concomitantly with increased thin-type spines, suggesting that dendritic spine maturation is impaired. Indeed, neurons lacking MAP1B show decreased miniature excitatory postsynaptic currents (mEPSCs) (Tortosa et al. 2011). Interestingly, MAP1B deficiency leads to increased stable microtubules at the expense of the more dynamic microtubules (González-Billault et al. 2001). This may be contributed in part by the interaction of MAP1B with the enzyme responsible for tubulin tyrosination, tubulin tyrosine ligase (Utreras et al. 2008).

The functional consequences of MTs entry into dendritic spines remain an open field. In a recent study, Hu et al. have shown that dynamic microtubules promote the accumulation of postsynaptic density (PSD)-95 in dendritic spines after BDNF treatments (Hu et al. 2011). NMDA receptor activation induces dendritic spine enlargement. Because this enlargement is more prominent in spines containing microtubules, it is suggested that NMDA-dependent microtubule polymerization promotes dendritic spine enlargement (Merriam et al. 2011). Interestingly, chemically induced long term depression suppresses the entry of microtubules into dendritic spines (Kapitein et al. 2011). About 1–2% of dendritic spines contain MTs, suggesting that MTs’ entry into dendritic spines is a transient and dynamic phenomenon (Gu et al. 2008; Hu et al. 2008; Jaworski et al. 2009; Tortosa et al. 2011). The presence of dynamic MTs in dendritic spines suggests a role of MT in the conversion of thin-type spines into mushroom-type spines. A potential microtubule-based transport mechanism occurring at dendritic spines would be complementary to the widely known myosin-dependent mechanism for material transport into spines (Dent et al. 2011). Moreover, microtubules in dendritic spines might be involved in the regulatory mechanism of actin dynamics within dendritic spines.

Role of actin filaments in dendritic spine formation

  1. Top of page
  2. Abstract
  3. Cytoskeletal structures in dendritic spines
  4. Role of actin filaments in dendritic spine formation
  5. Dendritic spine abnormalities in neuropsychiatric, neurodevelopmental, and neurodegenerative pathologies
  6. Future implications
  7. Acknowledgements
  8. References

From dendritic filopodia to spines

Dendritic filopodia show higher motility than dendritic spines, while dendritic spines show plastic morphological changes depending on synaptic activity. Dendritic filopodia have network-like organization of actin filaments (Korobova and Svitkina 2010), which is unusual for highly elongated membrane protrusions, where tight actin filament bundles, such as fascin-bundling actin filaments, are obligatory. The network-like organization is thought to make dendritic filopodia more elastic, allowing continuous morphological changes. On the other hand, dendritic spines contain stable actin filaments in the core region of dendritic spines. The stable actin filaments probably help keep the spine morphology constant until the occurrence of some special synaptic activity, such as tetanic stimulation, and the induction of synaptic plasticity. Although the properties of stable actin filaments in dendritic spines are not yet elucidated, drebrin is thought to be involved in the stabilization of actin filaments (Fig. 2).

Accumulation of DB-actin filaments at the nascent postsynaptic sites

There are two hypotheses as to how spine synapses are formed. One is that shaft synapses change to spine synapses, while the other maintains that presynaptic contact induces the change in filopodia into dendritic spines. In either case, soon after an axon comes into contact with a dendrite or a dendritic filopodium, presynaptic molecules such as bassoon and piccolo begin to accumulate. On the other hand, PSD-95 accumulation occurs in 1 h after the contact (Friedman et al. 2000).

One of the initial events to occur at the contact sites of dendritic filopodia or shaft is the accumulation of drebrin both in vivo (Aoki et al. 2005) and in vitro (Takahashi et al. 2003). In vitro analysis shows that these filopodia have DB-actin clusters, but lack scaffold proteins such as PSD-95 (Takahashi et al. 2003), indicating that these filopodia are different from mature dendritic spines (Fig. 2c and d). Once DB-actin filament clusters are formed, PSD-95 and glutamate receptors are accumulated into these clusters (Mizui et al. 2005). On the other hand, when the cluster formation is inhibited by the suppression of drebrin expression, accumulation of PSD-95 at the postsynaptic sites is suppressed (Takahashi et al. 2003). Interestingly, the excitatory synaptic activity is necessary for the cluster formation of DB-actin filaments at postsynaptic sites (Takahashi et al. 2009). These suggest that the cluster formation of DB-actin filaments is one of the initial events occurring at the nascent excitatory postsynaptic site and plays a pivotal role in spine formation. Although the molecular mechanism is not fully understood, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-dependent stabilization of drebrin has been shown to be involved in the mechanism by means of fluorescence recovery after photobleaching analysis (Takahashi et al. 2009).

Roles of Rac1A and RhoA in actin filaments in dendritic spines

As Luo's group showed that Rac1 and Rho functions are essential to promote dendritic spine formation (Nakayama et al. 2000), the role of small Rho GTPases in the formation of dendritic spines has been extensively reviewed (Luo 2002; Newey et al. 2005; Tada and Sheng 2006; Yoshihara et al. 2009). Rac1 inactivation leads to the progressive elimination of dendritic spines, while RhoA activation promotes a simplification of dendritic branching (Nakayama et al. 2000). Recently, using two-photon lifetime microscopy, Murakoshi et al. (2011) measured the activities of small Rho GTPases at dendritic spines. Both RhoA and Cdc42 activities rely on transient CamKII-activity to regulate spine dynamic properties. MAP1B can also promote actin microfilament polymerization through a mechanism that involves the participation of small GTPases Rac1/Cdc42 and RhoA (Montenegro-Venegas et al. 2010). Interestingly, MAP1B binds to Tiam1, a guanine exchanging factor that promotes Rac1 activity (Henríquez et al. 2012).

Morphological changes in dendritic spines are thought to be linked to information processing, and the regulation of actin dynamics, therefore, would be crucial in controlling information processing. As a matter of fact, long-term potentiation (LTP) induces actin polymerization, and consequently increases the volume of dendritic spines. A change in dendritic spine volume correlates with a shift in the ratio of actin monomers and actin filaments (Okamoto et al. 2004). In addition, NMDA receptor activation induces the transient translocation of drebrin from dendritic spine head to the parent dendrite, causing the reorganization of actin cytoskeleton in dendritic spines (Sekino et al. 2006). Among several actin-regulating proteins that control dendritic spine morphogenesis, ADF/cofilin is essential to maintain a soluble pool of actin monomers. ADF/cofilin promotes actin turnover and regulates dendritic spine morphology (Hotulainen et al. 2009). ADF/cofilin functions are regulated by serine 3 phosphorylation by LIM kinase 1, which inhibits ADF/cofilin function (Arber et al. 1998). Inactivation of LIMK1 by gene targeting results in abnormal dendritic spine density and morphology, which is characterized by the presence of abundant thin-type spines, impairing normal synaptic transmission (Meng et al. 2002).

LIMK and ADF/cofilin are effector proteins, which are downstream of Rac and RhoA signaling pathway (González-Billault et al. 2012). It has been shown that RhoA activity is required for LTP in a mechanism involving ADF/cofilin phosphorylation (Rex et al. 2009). Therefore, RhoA may promote actin stabilization by enhancing ADF/cofilin phosphorylation. Concomitantly, Rac1 and cdc42 may also contribute to the inhibition of ADF/cofilin activity (Rex et al. 2009).

Competitive role of drebrin and ADF/cofilin in dendritic spines

Drebrin has an ADF/cofilin-homology domain in its N-terminal region and binds to actin filaments with similar KD (1.2 × 10−7 M) to tropomyosin (5 × 10−6 M) and ADF/cofilin (2 × 10−7 M) (Ishikawa et al. 1994). While ADF/cofilin binds to both actin monomer and actin filaments, drebrin does not bind to actin monomer. In addition, drebrin binds to actin filaments via a unique actin-binding domain other than ADF/cofilin-homology domain (Hayashi et al. 1999). Interestingly, an actin protomer in the filament has two drebrin-binding sites, and thus each drebrin molecule can bind either one protomer or two protomers. DB-actin filaments can form five different filament structures (Grintsevich et al. 2010).

Drebrin and ADF/cofilin competitively bind to actin filaments, and the pitch of ADF/cofilin-binding actin filaments (28.7 nm) is much shorter than that of DB-actin filaments (Sharma et al. 2011). Dephosphorylation of ADF/cofilin diminishes its actin-binding activity, but that of drebrin does not affect its actin-binding activity. Thus, it is suggested that the regulation of the balance between drebrin and ADF/cofilin plays a pivotal role in actin dynamics in dendritic spines (Fig. 2e and f).

Dendritic spine abnormalities in neuropsychiatric, neurodevelopmental, and neurodegenerative pathologies

  1. Top of page
  2. Abstract
  3. Cytoskeletal structures in dendritic spines
  4. Role of actin filaments in dendritic spine formation
  5. Dendritic spine abnormalities in neuropsychiatric, neurodevelopmental, and neurodegenerative pathologies
  6. Future implications
  7. Acknowledgements
  8. References

Several neuropsychiatric, neurodevelopmental and neurodegenerative diseases show alterations in the morphology of dendrites. These changes include abnormal dendritic branching, fragmentation of dendrites and altered morphology of dendritic spines. This is perfectly exemplified in Fragile X syndrome and Down syndrome. The pathologies of these diseases are accompanied by the decrease in mushroom-type spines and the concomitant increase in thin-type spines (Irwin et al. 2000; Kaufmann and Moser 2000). Fragile X mental retardation protein, the protein responsible for Fragile X syndrome, binds and regulates the activity of cytoplasmic FMR1-interacting protein 1 (CYFIP1), a Rac1 effector protein (Schenck et al. 2003). Interestingly, mutations in other genes related to Rho GTPases functions are linked to non-syndromic mental retardation such as oligophrenin-1, which is a Rho GAP protein (Billuart et al. 1998), and α-PAK-interactive exchange factor (Pix), a guanine exchange factor for Rac (Manser et al. 1998). LIMK, a protein kinase activated by small GTPases RhoA and Rac1, is mutated in Williams syndrome leading to mental retardation (Bellugi et al. 1999).

The morphology and density of dendritic spines are altered also in autism spectrum disorders (ASD). In humans, alterations in neurexin and neuroligin genes are implicated in autism (Südhof 2008). Neuroligin-3 and neuroligin-4 are adhesion proteins present at postsynaptic sites, which are mutated in siblings with ASD (Jamain et al. 2003). The expression of mutated forms of neuroligin-3 and neurologin-4 in cultured neurons increases dendritic spine density (Chih et al. 2004). Similarly, mutations in neurexin 1, the presynaptic binding partner for neuregulins, also lead to abnormal dendritic spine density (Südhof 2008). Shank scaffolding proteins have also been linked to ASD (Durand et al. 2007; Sato et al. 2012). Shank2 and Shank3 mutant variants lead to increased dendritic spine size and density, respectively (Roussignol et al. 2005; Steiner et al. 2008).

Finally, neurodegenerative conditions such as Alzheimer's disease (AD) also display dendritic spine alterations. The most accepted risk factor for AD is the allele ε4 of the apolipoprotein E (APOE). ApoE ε4 shows reduced density of dendritic spines (Ji et al. 2003). In contrast, the over-expression of the allele e2 in the mouse model of AD can reverse the dendritic spine pathology (Lanz et al. 2003).

Drebrin and cofilin are also involved in AD (for review, see Kojima and Shirao 2007). Drebrin level is markedly reduced in the brains of AD (Harigaya et al. 1996; Hatanpaa et al. 1999; Counts et al. 2006). Furthermore, various studies using AD animal models indicate that drebrin is involved in the pathogenesis of AD (Calon et al. 2004; Mahadomrongkul et al. 2005; Lacor et al. 2007). It has been recently reported that drebrin A has a causal role in compromising activity-dependent glutamate receptor trafficking in the AD animal model (Lee and Aoki, 2012). Similarly, cofilin phosphorylation is altered in cultured cells exposed to Aβ peptide or in the mouse model of AD (Minamide et al. 2000; Heredia et al. 2006; Mendoza-Naranjo et al. 2012). Interestingly, drebrin is also reduced in Down syndrome (Shim and Lubec 2002). In addition, the drebrin gene (dbn1) has a cross-talking point of basic helix-loop-helix-PAS transcriptional factor related to Down syndrome pathology, such as NXF (activation) and Sim2 (repression), in its promoter regions (Ooe et al. 2004).

Another key molecule to regulate actin dynamics in dendritic spines is the protein kinase PAK, which is a downstream effector of Rac1. Both in animal models recapitulating AD and brain samples derived from post-mortem patients, PAK activation is markedly reduced (Zhao et al. 2006). Moreover, PAK1 and PAK3 promote the formation and growth of dendritic spines by regulating the phosphorylation of the myosin II regulatory light chain kinase and stimulating myosin II (Zhang et al. 2005).

Therefore, a likely working hypothesis is that aberrant regulation of cytoskeleton dynamics in spines contributes to several pathological conditions that affect dendritic spine morphology, thus preventing appropriate synaptic function and plasticity.

Future implications

  1. Top of page
  2. Abstract
  3. Cytoskeletal structures in dendritic spines
  4. Role of actin filaments in dendritic spine formation
  5. Dendritic spine abnormalities in neuropsychiatric, neurodevelopmental, and neurodegenerative pathologies
  6. Future implications
  7. Acknowledgements
  8. References

Since their discovery, dendritic spines have captured the attention of neurobiologists. Containing thousands of concentrated proteins, they are the site for excitatory synaptic transmission. Over the last few years, newfound information regarding the local regulation of cytoskeleton, signaling complex, and receptor endocytosis/recycling has provided vital clues to understanding the normal and pathological functions of dendritic spines. However, many questions still remain unanswered. What is the molecular mechanism that promotes maturation and/or stabilization of dendritic spines? Can signaling protein complexes locally alter both actin and microtubule dynamics in dendritic spines? Which hubs would be required to simultaneously control receptor endocytosis, cytoskeleton dynamics, protein synthesis, and signaling cascades? These and other intriguing questions will likely be answered in the coming years, helping sustain the interest of cellular-molecular neurobiologist in this tiny, but tremendously important domain.


  1. Top of page
  2. Abstract
  3. Cytoskeletal structures in dendritic spines
  4. Role of actin filaments in dendritic spine formation
  5. Dendritic spine abnormalities in neuropsychiatric, neurodevelopmental, and neurodegenerative pathologies
  6. Future implications
  7. Acknowledgements
  8. References
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