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Actin Filaments and Microtubules in Dendritic Spines JOURNAL OF NEUROCHEMISTRY | 2013 | 126 | 155–164 doi: 10.1111/jnc.12313 *Department of Neurobiology and Behavior, Gunma University Graduate School of Medicine, Maebashi, Japan †Laboratory of Cell and Neuronal Dynamics, Department of Biology, Faculty of Sciences, Universidad de Chile, Chile Abstract occurring at the nascent excitatory postsynaptic site, and Dendritic spines are small protrusions emerging from their plays a pivotal role in spine formation as well as small parent dendrites, and their morphological changes are GTPases. It has been recently reported that microtubules involved in synaptic plasticity. These tiny structures are transiently appear in dendritic spines in correlation with composed of thousands of different proteins belonging to synaptic activity. Interestingly, it is suggested that microtubule several subfamilies such as membrane receptors, scaffold dynamics might couple with actin dynamics. In this review, we proteins, signal transduction proteins, and cytoskeletal pro- will summarize the contribution of both actin filaments and teins. Actin filaments in dendritic spines consist of double helix microtubules to the formation and regulation of dendritic of actin protomers decorated with drebrin and ADF/cofilin, and spines, and further discuss the role of cytoskeletal deregula- the balance of the two is closely related to the actin dynamics, tion in neurological disorders. which may govern morphological and functional synaptic Keywords: actin, dendritic spine, microtubules, synaptic plasticity. During development, the accumulation of drebrin- plasticity. binding type actin filaments is one of the initial events J. Neurochem. (2013) 126, 155–164. Dendritic spines are small protrusions emerging from their mature neurons have dendritic spines capable of morpho- parent dendrites, and contain postsynaptic structures such as logical plasticity depending on synaptic activity (Fig. 2e postsynaptic density and actin filaments and, under certain and f). How does a neuron form dendritic spines? When a circumstances, microtubules. Dendritic spines observed in presynaptic terminal comes into contact with a filopodium, fixed brain tissue and cultured neurons show various shapes a cluster of actin filaments appears at the contact site in (Fig. 1a–c) and are generally classified into three types: the the filopodium (Fig. 2c and d). Eventually, the cluster- thin type having a slender neck and a small head, the containing processes change into mature dendritic spines mushroom type having a short neck and a relatively large (Takahashi et al. 2003). In this mini-review, we will head, and the stubby type having no neck. All these delineate the basic cytoskeletal elements in dendritic categories reflect a continuum rather than separate classes spines and discuss the role of cytoskeletons in the (Rochefort and Konnerth 2012). And in living neurons, spine dendritic spine formation, synaptic plasticity, and neuro- shapes easily interchange among the above three types. In logical disorders. other words, spine morphologies are snapshots of dynamic morphological changes. In fact, dendritic spines dynamically Received April 10, 2013; revised manuscript received May 13, 2013; change their morphology in response to synaptic transmis- accepted May 13, 2013. sion, which happens to be the structural basis of synaptic Address correspondence and reprint requests to Dr. Tomoaki Shirao, plasticity. Department of Neurobiology and Behavior, Gunma University Graduate Although at early developmental stages neurons form School of Medicine, Maebashi 371-8511, Japan. fi E-mails: [email protected]; [email protected] many thin lopodia on their dendrites (Fig. 2a and b), they Abbreviations used: AD, Alzheimer’s disease; ASD, autism spectrum are just similar to those emerging from non-neuronal cells disorders; DB-actin, drebrin-binding actin; LTP, long-term potentiation; and do not show any morphological plasticity. Only MAPs, microtubule-associated proteins. © 2013 International Society for Neurochemistry, J. Neurochem. (2013) 126, 155--164 155 156 T. Shirao and C. Gonzalez-Billault (a) (d) (b) PresynapƟc terminal (e) SynapƟc vesicles Glutamate receptors Spine PSD (c) drebrin IQGAP ? EB3 Microtubules MAP1B ? AcƟn filaments MAP2 ADF/cofilin DendriƟc shaŌ Fig. 1 (a) DiI labeling of a 21-day-in vitro hippocampal neuron. (b) with anti-drebrin antibody (M2F6). Blue shows microtubule-associated Enlarged images of the areas indicated by the square in (a). (c) Golgi proteins immunostained with anti-MAPs anti-serum. Note that yellow staining image of hippocampal neuron of the adult rat brain. (d) Triple signals indicate co-localization of drebrin and F-actin in dendritic spines. (e) staining images of a 21-day-in vitro hippocampal neuron. Red shows actin Schematic presentation of actin filaments, microtubules and postsynaptic filament stained with phalloidin. Green shows drebrin immunostained density (PSD). Scale bars are 20 lm in (a) and 2 lmin(b). (a) (b) (c)(d) (e) (f) Dynamic actin pool Stable actin pool PSD structure Presynaptic terminal Drebrin PSD95 ADF/cofilin Cortical actin in dendritic shaft Fig. 2 Schematic representation of dendritic spine formation from filament clusters are formed, postsynaptic density (PSD)-95 and dendritic filopodia. (a) and (b) are filopodia. A filopodium at early glutamate receptors are accumulated into these clusters in (d). (e) and developmental stages of a neuron is similar to that emerging from a (f) are mature spines. When DB-actin filament is predominant in the non-neuronal cell. When a presynaptic terminal contacts a filopodium, spine, the spine morphology is stable. Long-term potentiation (LTP) drebrin is accumulated at nascent contact sites in (b), (c) and (d) are signals might form mushroom-type spines in (e). When ADF/cofilin- immature spines. Drebrin-binding actin filaments form stable actin pool binding-actin filaments predominate, the spine morphology is unstable at postsynaptic site in (c). Once drebrin-binding actin (DB-actin) in (f). © 2013 International Society for Neurochemistry, J. Neurochem. (2013) 126, 155--164 Actin and microtubule in dendritic spine 157 Another possible mechanism is the capping of the barbed end Cytoskeletal structures in dendritic spines of an actin filament, which results in the inhibition of actin Overview of actin filaments polymerization at the barbed end. Relative facilitation of An actin filament consists of double helix of actin protomers actin depolymerization at the pointed end consequently decorated with its binding proteins. The physical and decreases the content of actin filaments. Interestingly, ADF/ biochemical properties of actin filaments are varied among cofilin is known to facilitate the actin depolymerization by different cell types and even among subcellular regions. This increasing the rate of dissociation from the pointed end of is not because actin molecule isoforms are different, but actin filaments as well as sequestering actin monomers because filament-binding proteins, such as tropomyosin and (Carlier et al. 1997). Because its actin-binding activity is drebrin, are so (Shirao et al. 1992; Sekino et al. 2007) and modulated by phosphorylation, the phosphorylation signals actin depolymerizing factor (ADF)/cofilin (Bamburg et al. might cause the locally biased actin-filament depolymerizing 1999). activity of ADF/cofilin. In addition, an actin filament has a polarity. It has a barbed Actin filaments can form various kinds of higher order end and a pointed end, which are named after the electron structures. In cooperation with actin-bundling proteins, such microscopic image of actin filaments decorated with heavy as a-actinin and fascin, they form a straight bundle. a- mero-myosin as a metaphor for the arrowhead (Huxley 1963; actinin-mediated actin bundle is a straight long bundle, Ishikawa et al. 1969). It is known that actin filaments keep typically linking adhesion plaques within a cell. Fascin forms treadmilling reaction (Wegner 1976) when their ends are not a thin actin bundle consisting of five to six filaments, a capped by actin-capping proteins. According to the tread- typical actin structure found in a filopodium of axonal growth milling reaction, actin protomers are continuously added cone (Sasaki et al. 1996). On the other hand, filamin forms a (polymerized) at the barbed end and removed (depolymer- meshwork of actin filaments (Nakamura et al. 2011). ized) at the pointed end (Pollard and Mooseker 1981). Protrusive motility of a cell generally proceeds by a Unique character of actin filaments in dendritic spines treadmilling reaction in cooperation with actin-binding Actin filaments are remarkably highly accumulated in a proteins (Achard et al. 2010), such as ADF/cofilin, actin- dendritic spine (head) compared with the parent dendrite related proteins Arp2 and Arp3 (Arp2/3) complex (Pollard (Fig. 1d and e). Although the accumulation mechanism has and Beltzner 2002), and WASP/Scar family (Symons et al. yet to be elucidated, it is known that actin filaments in 1996), when the filaments show isotropic orientation. dendritic spines have a unique character because of a high Fluorescent recovery after photobleaching revealed the rapid drebrin content (Sekino et al. 2007). turnover of actin in dendritic spines (Star et al. 2002). This Variations in the helical structure of actin filaments can be suggests that the treadmilling reaction of actin filament modulated by the binding of actin-binding proteins (Sharma occurs in dendritic spines. However, because a single- et al. 2012). The pitch of an
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