- Email: [email protected]
Postsynaptic actin and neuronal plasticity
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Postsynaptic actin and neuronal plasticity Andrew Matus In the adult brain, actin is concentrated in dendritic spines where it can produce rapid changes in their shape. Through various synaptic junction proteins, this postsynaptic actin is linked to neurotransmitter receptors, influencing their function and, in turn, being influenced by them. Thus, the actin cytoskeleton is emerging as a key mediator between signal transmission and anatomical plasticity at excitatory synapses. Addresses Friedrich Miescher Institute, PO Box 2543, 4002 Basel, Switzerland; e-mail: [email protected] Current Opinion in Neurobiology 1999, 9:561–565 0959-4388/99/$ — see front matter © 1999 Elsevier Science Ltd. All rights reserved. Abbreviations AMPA α-amino-3-hydroxy-5-methyl-4-isoxazole propionate GFP green fluorescent protein LTP long-term potentitation NMDA N-methyl-D-aspartate p70S6K p70 S6 kinase PDZ PSD-95, Dlg, ZO-1 (protein interaction module) PSD postsynaptic density
Introduction At synapses in the brain, actin is highly concentrated in dendritic spines — the tiny protrusions on the surface of dendrites that form the postsynaptic contact sites for glutamatergic synapses [1,2]. The special nature of this association is underlined by evidence showing that β- and γ-cytoplasmic actin, the two isoforms expressed in neurons, are targeted specifically to spines through a sequence-dependent mechanism [3]. What is the purpose of this high concentration of actin in dendritic spines? In many cells, cytoplasmic actins are associated with surface motility, and time-lapse recordings made using actin tagged with green fluorescent protein (GFP) have shown that spines undergo rapid, actin-dependent shape changes [4••]. These findings suggest a role for actin in experiencedependent changes in spine shape, which have been studied for many years (see e.g. [5–7]) and which have been proposed as a cellular basis for the alterations in synaptic connectivity that are thought to underlie learning and memory [8–10]. An important property of actin, in this respect, is its ability to alternate between supporting structures, such as filopodia, that are motile and other structures, such as stress fibres, that stabilize cell shape. This property could be particularly significant for its role at synapses, where a regulated balance between plasticity and stability is essential for allowing established connections to function reliably, while at the same time retaining sufficient flexibility to form new activity-induced relationships. Crucial to this versatility are a large number of actin-binding
proteins that regulate actin polymerization and control the arrangement of the filaments it forms. In neurons, these include a growing catalogue of proteins — some already familiar from other contexts, others newly discovered [11,12,13•] — that link actin filaments to proteins of the postsynaptic density (PSD), the plaque-like structure attached to the postsynaptic membrane, including receptors for glutamate, the neurotransmitter at these synapses. In this review, I consider the relationships between the actin cytoskeleton and molecules (both neurotransmitter receptors and structural proteins) that are situated postsynaptically in dendritic spines.
Glutamate receptors and the actin cytoskeleton Both of the major ion-channel-linked glutamate receptors at spine synapses — NMDA- and AMPA-type glutamate receptors — are closely associated with the actin cytoskeleton. The entry of Ca2+ through activated NMDA receptor channels depolymerizes postsynaptic actin [14,15•] and produces a negative feedback effect on the receptor itself, causing a gradual rundown of its associated Ca2+ activity [16]. Implicated in this processes is the actin-bundling protein α-actinin-2, which binds to actin through its amino terminus and to the NR1 subunit of NMDA receptors through its central rod domain [17]. Ca2+ antagonizes this interaction by binding to α-actinin-2 both directly [18] and indirectly via calmodulin, which competes for the NR1-binding site [17,19]. Recent studies using dominantnegative forms of α-actinin-2 provide strong evidence that Ca2+-induced rundown of NMDA receptor channel activity is largely the result of breaking the α-actinin-2 link between actin filaments and the receptor itself [18,19]. This finding is further supported by a recent study on cultured neurons showing that latrunculin A, a powerful actin-depolymerizing drug, simultaneously dissociates αactinin-2 from receptor clusters and disperses NMDA receptors away from synaptic sites [20•]. The influence of α-actinin-2 on NMDA receptor function is presumably restricted by α-actinin-2’s limited distribution in the brain; for example, in the hippocampus, its expression is high in area CA2 but extremely low in areas CA1 and CA3 [21]. Elsewhere, other actin-binding proteins may influence NMDA receptor function. Spectrin, a more widely distributed actin-bundling protein, binds NMDA receptors at a site distinct from that used by αactinin-2, and this interaction is also antagonized by Ca2+ [22]. NMDA receptors are also influenced by gelsolin, an actin-binding protein that severs actin filaments in a Ca2+dependent manner. In hippocampal neurons from gelsolin knockout mice, Ca2+ influx through NMDA receptors is increased because the normal channel inactivation that
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results from Ca 2+-induced actin depolymerization is reduced [23]. This increase in Ca2+ influx is probably attributable to the fact that actin filaments are partially protected from Ca2+-induced depolymerization in these gelsolin-deprived cells. AMPA receptors also are sensitive to the assembly state of actin. Like NMDA receptors, they are displaced from synaptic sites when actin filaments are depolymerized, but differences in their patterns of dispersal suggest that the two receptor types are linked to the actin cytoskeleton by distinct mechanisms [20•]. This observation is consistent with recently described differences in their synaptic expression patterns. During postnatal development, most synapses initially display only NMDA receptor activity, with AMPA responses emerging later through an activitydependent mechanism that involves the physical recruitment of AMPA receptor to postsynaptic sites [24,25]. Very recently, it has been shown in brain slices maintained in vitro that tetanic stimulation sufficient to produce NMDA-receptor-dependent long-term potentiation (LTP) of synaptic transmission induces rapid delivery of GFP-labelled AMPA receptors molecules to dendritic spines [26••]. The involvement of actin filaments in these changes in receptor expression is suggested by the effects of directly perfusing actin-depolymerizing drugs into neurons, which produce a decrease in both the magnitude of LTP and in AMPA-receptor-mediated synaptic transmission, without affecting NMDA receptor responses [27]. AMPA receptors appear to remain labile even after synapses are established, as it has been found that AMPA receptors are lost reversibly from synaptic sites within 5 min following their activation, resulting in a transitory 50% decrease in postsynaptic current [28]. AMPA receptor expression is also linked to synaptic morphology. Synapses smaller than 180 nm across have been found to contain only NMDA receptors; above this size, the number of immunohistochemically detectable AMPA receptors increases linearly with synaptic diameter [29]. Increased AMPA receptor numbers are also associated with synapses containing perforated PSDs [30], a feature that has been proposed as a contributory mechanism to activity-induced synaptic plasticity [31,32,33•].
Links to synaptic junctions One molecule that may link AMPA receptors to the actin cytoskeleton is SAP97, one of the large number of synaptic junction proteins with PDZ domains (reviewed in [34]), which binds to the actin cytoskeleton through its amino terminus and to the GluR1 AMPA receptor subunit through its PDZ domain [35•]. SAP97 is also expressed at intercellular junctions in epithelial cells, where it associates with molecular complexes formed between the Ca2+-dependent cell adhesion molecule cadherin and its intracellular partner catenin [36]. Nevertheless, its primary association is with the actin cytoskeleton. Actin/SAP97 adducts form first and are then recruited to focal contact
sites by cadherin/catenin complexes when intercellular junctions are formed [37]. In neurons, cadherin/catenin complexes to which SAP97 binds are located at the borders of active zones, where presynaptic vesicle release sites are in register with postsynaptic neurotransmitter receptors [38]. The linkage of SAP97 to these complexes may be important in determining the structural relationship of AMPA receptors and the actin cytoskeleton in the postsynaptic membrane. Another PDZ domain protein with an intriguing relationship to both actin and AMPA receptors is neurabin (short for neural tissue actin-binding protein), which exists in two forms: neuron-specific neurabin I and the more widely expressed neurabin II/spinophilin [39,40]. Like SAP-97, neurabin has an actin-binding domain at its amino terminus; however, its carboxyl terminus contains coiled-coil domains through which it forms homo-oligomers, allowing it to also function as an actin-bundling protein [40,41]. Through its PDZ domain, neurabin binds to several other proteins, such as protein phosphatase 1 (PP1), whose postsynaptic actions include limiting the rundown of AMPA receptor channel activity. This effect is increased when PP1 binds to neurabin II/spinophilin, presumably because it is then anchored through postsynaptic actin filaments in the vicinity of phosphorylated substrate sites on AMPA receptors [42]. A second neurabin-binding partner is p70 S6 kinase (p70S6K) [43], an enzyme that regulates the translation of a set of abundant mRNAs that contain polypyrimidine tracts in their 5′-untranslated domains [44]. The activity of p70S6K increases substantially when it binds to neurabin [43], suggesting a possible link between the actin cytoskeleton and the control of translational activity in neurons. Anchoring of neurabin–p70S6K complexes to spine-associated actin would place p70S6K close to clusters of polyribosomes present at the bases of dendritic spines that have long been discussed in terms of their possible contribution to local protein synthesis (see [45]).
Morphological plasticity Dynamic imaging of living neurons has revolutionized the study of anatomical plasticity at synapses by making it possible to observe directly the events underlying activity-dependent changes in dendritic spine morphology that previously could only be inferred from examining fixed tissue. A significant early discovery was the motile behaviour of filopodia-like protrusions at the surface of developing dendrites, from which mature dendritic spines develop [46,47]. Two recent studies have extended this observation by showing that stimulation protocols that produce NMDA-receptor-dependent LTP in brain slices can induce the formation of new spine-like structures on dendrites [48••,49••]. Both the motility and relatively rapid appearance of these protrusions suggest that their outgrowth depends on an actin-based mechanism, although this has not yet been demonstrated. These studies did not
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Figure 1 Schematic showing the possible influence of glutamate receptor activation on dendritic spine actin. On the basis of recent data, this diagram summarizes the potential effects of NMDA- and AMPA-type glutamate receptors on the assembly and motility of postsynaptic actin at glutamatergic excitatory synapses. (a) During development, synaptic vesicles in swellings (synaptic boutons) on axons release glutamate, which binds to NMDA receptors on the surfaces of developing dendrites. (b) Actin filaments assemble at these sites and drive the outgrowth of filopodial-like dendritic spine precursors. This depends on strong activation of NMDA recpetors, which can be experimentally induced by high-frequency stimulation protocols that produce LTP of synaptic transmission. This same NMDA-receptor-dependent stimulation induces the acquisition of postsynaptic AMPA receptors. Activation of AMPA receptors by glutamate at levels subthreshold for action potential firing leads to stabilization of motile spines, which then adopt the ‘classical’ round-head morphology. As indicated by the bidirectional arrows, both AMPA-receptor-dependent stabilization of spine morphology and maintenance of spine number appear to be reversible. See text for additional details.
Activity-dependent modification of dendritic spine actin (a) Synaptic vesicle Axon NMDA receptor
An important issue concerns the relationship between these rapid, actin-dependent changes in spine morphology and long-term changes in circuit connectivity. It has long been known that spines that regress when their axonal inputs are cut can subsequently re-emerge when sprouting axons from neighbouring pathways re-innervate vacated postsynaptic sites (see e.g. [51]). This phenomenon has recently been examined in hippocampal slice cultures in which minute lesions produced both a reduction in total spine number and a decline in large mushroom-shaped spines, which were replaced by stubby remnants [52••]. This regression could be mimicked by blocking neurotransmitter release with botulinum toxin, and, conversely, the spine loss produced by lesioning could be avoided by adding low concentrations of AMPA to the cultures, suggesting that low-level AMPA receptor stimulation is both necessary and sufficient for spine maintenance [52••].
Dendrite
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show that these newly generated spines make synaptic contacts, although this is likely because nascent spines in brain tissue of equivalent age to the tissue slices used in these studies are contacted by axons [50]. Actin-dependent shape changes in dendritic spines have been demonstrated directly in time-lapse recordings of neurons transfected with GFP-tagged actin [4••]. The spines analysed in this study were shown to be contacted by presynaptic terminals, thus demonstrating that dendritic spines at established synapses retain the capacity for morphological plasticity. An interesting feature of this plasticity is its rapidity: changes in spine shape were detectable between frames taken less than 2 s apart. More recent observations of GFP–actin-expressing neurons in our laboratory have shown that, in contrast to the NMDAreceptor-dependent induction of new spines, actin-based shape changes in spines at established synapses are inhibited by AMPA receptor activation (M Fischer, S Kaech, U Wagner, A Matus, unpublished data).
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Together, these recent experiments suggest a scenario in which spines are initially produced as motile structures in response to NMDA receptor activation and, subsequently, become morphologically stabilized by AMPA-receptormediated transmission (Figure 1).
Conclusions The existence of actin-dependent changes in dendritic spine morphology is now firmly established. The purpose of this cytoskeletal plasticity is almost certainly to adapt circuit connectivity to varying patterns of stimulation, either by modulating transmission efficiency of existing
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synapses or by removing redundant dendritic spines and producing new ones at other sites. In principle, both effects could co-exist as intermediate and extreme states of the same actin-based morphogenic process. The growing evidence for activity-dependent changes in connectivity at glutamatergic synapses in both the developing and the adult brain already point in this direction [53•,54•] and provides good reason for continuing to explore the role of postsynaptic actin.
15. Halpain S, Hipolito A, Saffer L: Regulation of F-actin stability in • dendritic spines by glutamate receptors and calcineurin. J Neurosci 1998, 18:9835-9844. This study implicates actin in early events of excitotoxic neuron damage. The authors report that exposing hippocampal neurons to high concentrations (50 µM) of NMDA caused both loss of synaptic actin and disappearance of dendritic spines within 5 min. The effects were inhibited by blockers of calcineurin, implicating this Ca2+-dependent phosphatase in regulating postynaptic actin. 16. Rosenmund C, Westbrook GL: Calcium-induced actin depolymerization reduces NMDA channel activity. Neuron 1993, 10:805-814. 17.
Acknowledgements The author wishes to acknowledge his debt to Professor EG Gray, who died recently, for introducing him to the concepts of synaptic organization.
References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as:
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10. Muller D: Ultrastructural plasticity of excitatory synapses. Rev Neurosci 1997, 8:77-93. 11. Mundel P, Heid HW, Mundel TM, Kruger M, Reiser J, Kriz W: Synaptopodin: an actin-associated protein in telencephalic dendrites and renal podocytes. J Cell Biol 1997, 139:193-204. 12. Shen K, Teruel MN, Subramanian K, Meyer T: CaMKIIbeta functions as an F-actin targeting module that localizes CaMKIIalpha/beta heterooligomers to dendritic spines. Neuron 1998, 21:593-606. 13. Hayashi K, Shirao T: Change in the shape of dendritic spines • caused by overexpression of drebrin in cultured cortical neurons. J Neurosci 1999, 19:3918-3925. Using GFP-tagging, the authors show that drebrin, an actin-binding protein, is targeted to dendritic spines through its actin-binding domain. Overexpression of drebrin induces filopodia on normally smooth epithelial cells and has a dramatic effect on dendritic spines, increasing their average length by up to 50% without changing their number. This is one of several recent papers testifying to the large number of proteins that influence the function of postsynaptic actin. 14. Shorte SL: N-methyl-D-aspartate evokes rapid net depolymerization of filamentous actin in cultured rat cerebellar granule cells. J Neurophysiol 1997, 78:1135-1143.
Wyszynski M, Lin J, Rao A, Nigh E, Beggs AH, Craig AM, Sheng M: Competitive binding of alpha-actinin and calmodulin to the NMDA receptor. Nature 1997, 385:439-442.
18. Krupp JJ, Vissel B, Thomas CG, Heinemann SF, Westbrook GL: Interactions of calmodulin and alpha-actinin with the NR1 subunit modulate Ca2+-dependent inactivation of NMDA receptors. J Neurosci 1999, 19:1165-1178. 19. Zhang S, Ehlers MD, Bernhardt JP, Su CT, Huganir RL: Calmodulin mediates calcium-dependent inactivation of N-methyl-Daspartate receptors. Neuron 1998, 21:443-453. 20. Allison DW, Gelfand VI, Spector I, Craig AM: Role of actin in • anchoring postsynaptic receptors in cultured hippocampal neurons: differential attachment of NMDA versus AMPA receptors. J Neurosci 1998, 18:2423-2436. Presents a detailed analysis of the effects of actin depolymerization on the spatial arrangement of postsynaptic glutamate receptors. Provides essential background information for recent studies on the constrasting roles of NMDA and AMPA receptors in activity-induced changes in synaptic strength. 21. Wyszynski M, Kharazia V, Shanghvi R, Rao A, Beggs AH, Craig AM, Weinberg R, Sheng M: Differential regional expression and ultrastructural localization of alpha-actinin-2, a putative NMDA receptor-anchoring protein, in rat brain. J Neurosci 1998, 18:13831392. 22. Wechsler A, Teichberg VI: Brain spectrin binding to the NMDA receptor is regulated by phosphorylation, calcium and calmodulin. EMBO J 1998, 17:3931-3939. 23. Furukawa K, Fu W, Li Y, Witke W, Kwiatkowski DJ, Mattson MP: The actin-severing protein gelsolin modulates calcium channel and NMDA receptor activities and vulnerability to excitotoxicity in hippocampal neurons. J Neurosci 1997, 17:8178-8186. 24. Liao D, Zhang X, O’Brien R, Ehlers MD, Huganir RL: Regulation of morphological postsynaptic silent synapses in developing hippocampal neurons. Nat Neurosci 1999, 2:37-43. 25. Petralia RS, Esteban JA, Wang YX, Partridge JG, Zhao HM, Wenthold RJ, Malinow R: Selective acquisition of AMPA receptors over postnatal development suggests a molecular basis for silent synapses. Nat Neurosci 1999, 2:31-36. 26. Shi SH, Hayashi Y, Petralia RS, Zaman SH, Wenthold RJ, Svoboda K, •• Malinow R: Rapid spine delivery and redistribution of AMPA receptors after synaptic NMDA receptor activation. Science 1999, 284:1811-1816. The title says it all. Using AMPA receptors labelled with GFP were delivered to neurons in brain slices maintained in vitro so that their distribution could be studied in living cells. This suggests that the signal strength increase produced by this well-known stimulation paradigm depends upon directed delivery of AMPA receptors to postsynaptic sites at activated synapses. 27.
Kim CH, Lisman JE: A role of actin filaments in synaptic transmission and long-term potentiation. J Neurosci 1999, 19:4314-4324.
28. Lissin DV, Carroll RC, Nicoll RA, Malenka RC, von Zastrow M: Rapid, activation-induced redistribution of ionotropic glutamate receptors in cultured hippocampal neurons. J Neurosci 1999, 19:1263-1272. 29. Takumi Y, Ramirez-Leon V, Laake P, Rinvik E, Ottersen OP: Different modes of expression of AMPA and NMDA receptors in hippocampal synapses. Nat Neurosci 1999, 2:618-624. 30. Desmond NL, Weinberg RJ: Enhanced expression of AMPA receptor protein at perforated axospinous synapses. Neuroreport 1998, 9:857-860. 31. Cohen RS, Siekevitz P: Form of the postsynaptic density. A serial section study. J Cell Biol 1978, 78:36-48.
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32. Geinisman Y, Detoledo-Morrell L, Morrell F, Persina IS, Beatty MA: Synapse restructuring associated with the maintenance phase of hippocampal long-term potentiation. J Comp Neurol 1996, 368:413-423.
43. Burnett PE, Blackshaw S, Lai MM, Qureshi IA, Burnett AF, Sabatini DM, Snyder SH: Neurabin is a synaptic protein linking p70 S6 kinase and the neuronal cytoskeleton. Proc Natl Acad Sci USA 1998, 95:8351-8356.
33. Sorra KE, Fiala JC, Harris KM: Critical assessment of the • involvement of perforations, spinules, and spine branching in hippocampal synapse formation. J Comp Neurol 1998, 398:225-240. A detailed study of several ultrastructural features of spine synapses that considers several traditional models of anatomical synaptic plasticity and provides a comprehensive survey of recent literature. The electron microscopy data support a role for perforations and spinules in transient morphological changes.
44. Jefferies HB, Reinhard C, Kozma SC, Thomas G: Rapamycin selectively represses translation of the “polypyrimidine tract” mRNA family. Proc Natl Acad Sci USA 1994, 91:4441-4445.
34. Craven SE, Bredt DS: PDZ proteins organize synaptic signaling pathways. Cell 1998, 93:495-498. 35. Leonard AS, Davare MA, Horne MC, Garner CC, Hell JW: SAP97 is • associated with the alpha-amino-3-hydroxy-5-methylisoxazole-4propionic acid receptor GluR1 subunit. J Biol Chem 1998, 273:19518-19524. Together with [33•,34], the authors describe a molecular mechanism involving SAP97, which is capable of coupling AMPA receptors to the actin cytoskeleton and to the synaptic junction. This mechanism could be important in recently described activity-dependent changes in their expression at the synapse (see [24,25]). 36. Reuver SM, Garner CC: E-cadherin mediated cell adhesion recruits SAP97 into the cortical cytoskeleton. J Cell Sci 1998, 111:1071-1080. 37.
Wu H, Reuver SM, Kuhlendahl S, Chung WJ, Garner CC: Subcellular targeting and cytoskeletal attachment of SAP97 to the epithelial lateral membrane. J Cell Sci 1998, 111:2365-2376.
38. Uchida N, Honjo Y, Johnson KR, Wheelock MJ, Takeichi M: The catenin/cadherin adhesion system is localized in synaptic junctions bordering transmitter release zones. J Cell Biol 1996, 135:767-779. 39. Allen PB, Ouimet CC, Greengard P: Spinophilin, a novel protein phosphatase 1 binding protein localized to dendritic spines. Proc Natl Acad Sci USA 1997, 94:9956-9961. 40. Nakanishi H, Obaishi H, Satoh A, Wada M, Mandai K, Satoh K, Nishioka H, Matsuura Y, Mizoguchi A, Takai Y: Neurabin: a novel neural tissue-specific actin filament-binding protein involved in neurite formation. J Cell Biol 1997, 139:951-961.
45. Steward O, Falk PM, Torre ER: Ultrastructural basis for gene expression at the synapse: synapse-associated polyribosome complexes. J Neurocytol 1996, 25:717-734. 46. Ziv NE, Smith SJ: Evidence for a role of dendritic filopodia in synaptogenesis and spine formation. Neuron 1996, 17:91-102. 47.
Dailey ME, Smith SJ: The dynamics of dendritic structure in developing hippocampal slices. J Neurosci 1996, 16:2983-2994.
48. Maletic-Savatic M, Malinow R, Svoboda K: Rapid dendritic •• morphogenesis in CA1 hippocampal dendrites induced by synaptic activity. Science 1999, 283:1923-1917. See annotation [49••]. 49. Engert F, Bonhoeffer T: Dendritic spine changes associated with •• hippocampal long-term synaptic plasticity. Nature 1999, 399:66-70. Together with [48••], this paper shows for the first time that new spine-like protrusions can be induced on dendrites by high-frequency, NMDA-receptor-dependent stimulation, which is known to produce increases in synaptic signal strength. These studies provide the clearest evidence to date for a link between synaptic transmission and changes in synaptic connectivity. 50. Fiala JC, Feinberg M, Popov V, Harris KM: Synaptogenesis via dendritic filopodia in developing hippocampal area CA1. J Neurosci 1998, 18:8900-8911. 51. Parnavelas JG, Lynch G, Brecha N, Cotman CW, Globus A: Spine loss and regrowth in hippocampus following deafferentation. Nature 1974, 248:71-73. 52. McKinney RA, Capogna M, Durr R, Gahwiler BH, Thompson SM: •• Miniature synaptic events maintain dendritic spines via AMPA receptor activation. Nat Neurosci 1999, 2:44-49. Using hippocampal slice cultures, the authors show that either lesioning axons or blocking postsynaptic AMPA receptors leads to extensive loss of dendritic spines and shrinkage of those that remain. These effects were not produced by blocking NMDA receptors. Conversely, the effect of lesioning could be rescued by supplying cultures with small quantities of AMPA. The results implicate subthreshold AMPA receptor activation, produced by spontaneous quantal neurotransmitter release, in spine maintenance.
41. Satoh H, Nakanishi H, Obaishi H, Wada M, Takahashi K, Satoh K, Hirao K, Nishioka H, Hata Y, Mizoguchi A, Takai Y: NeurabinII/spinophilin. An actin filament-binding protein with one PDZ domain localized at cadherin-based cell-cell adhesion sites. J Biol Chem 1998, 273:3470-3475.
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42. Yan Z, Hsieh-Wilson L, Feng J, Tomizawa K, Allen PB, Fienberg AA, Nairn AC, Greengard P: Protein phosphatase 1 modulation of neostriatal AMPA channels: regulation by DARPP-32 and spinophilin. Nat Neurosci 1999, 2:13-17.
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Postsynaptic actin and neuronal plasticity Andrew Matus In the adult brain, actin is concentrated in dendritic spines where it can produce rapid changes in their shape. Through various synaptic junction proteins, this postsynaptic actin is linked to neurotransmitter receptors, influencing their function and, in turn, being influenced by them. Thus, the actin cytoskeleton is emerging as a key mediator between signal transmission and anatomical plasticity at excitatory synapses. Addresses Friedrich Miescher Institute, PO Box 2543, 4002 Basel, Switzerland; e-mail: [email protected] Current Opinion in Neurobiology 1999, 9:561–565 0959-4388/99/$ — see front matter © 1999 Elsevier Science Ltd. All rights reserved. Abbreviations AMPA α-amino-3-hydroxy-5-methyl-4-isoxazole propionate GFP green fluorescent protein LTP long-term potentitation NMDA N-methyl-D-aspartate p70S6K p70 S6 kinase PDZ PSD-95, Dlg, ZO-1 (protein interaction module) PSD postsynaptic density
Introduction At synapses in the brain, actin is highly concentrated in dendritic spines — the tiny protrusions on the surface of dendrites that form the postsynaptic contact sites for glutamatergic synapses [1,2]. The special nature of this association is underlined by evidence showing that β- and γ-cytoplasmic actin, the two isoforms expressed in neurons, are targeted specifically to spines through a sequence-dependent mechanism [3]. What is the purpose of this high concentration of actin in dendritic spines? In many cells, cytoplasmic actins are associated with surface motility, and time-lapse recordings made using actin tagged with green fluorescent protein (GFP) have shown that spines undergo rapid, actin-dependent shape changes [4••]. These findings suggest a role for actin in experiencedependent changes in spine shape, which have been studied for many years (see e.g. [5–7]) and which have been proposed as a cellular basis for the alterations in synaptic connectivity that are thought to underlie learning and memory [8–10]. An important property of actin, in this respect, is its ability to alternate between supporting structures, such as filopodia, that are motile and other structures, such as stress fibres, that stabilize cell shape. This property could be particularly significant for its role at synapses, where a regulated balance between plasticity and stability is essential for allowing established connections to function reliably, while at the same time retaining sufficient flexibility to form new activity-induced relationships. Crucial to this versatility are a large number of actin-binding
proteins that regulate actin polymerization and control the arrangement of the filaments it forms. In neurons, these include a growing catalogue of proteins — some already familiar from other contexts, others newly discovered [11,12,13•] — that link actin filaments to proteins of the postsynaptic density (PSD), the plaque-like structure attached to the postsynaptic membrane, including receptors for glutamate, the neurotransmitter at these synapses. In this review, I consider the relationships between the actin cytoskeleton and molecules (both neurotransmitter receptors and structural proteins) that are situated postsynaptically in dendritic spines.
Glutamate receptors and the actin cytoskeleton Both of the major ion-channel-linked glutamate receptors at spine synapses — NMDA- and AMPA-type glutamate receptors — are closely associated with the actin cytoskeleton. The entry of Ca2+ through activated NMDA receptor channels depolymerizes postsynaptic actin [14,15•] and produces a negative feedback effect on the receptor itself, causing a gradual rundown of its associated Ca2+ activity [16]. Implicated in this processes is the actin-bundling protein α-actinin-2, which binds to actin through its amino terminus and to the NR1 subunit of NMDA receptors through its central rod domain [17]. Ca2+ antagonizes this interaction by binding to α-actinin-2 both directly [18] and indirectly via calmodulin, which competes for the NR1-binding site [17,19]. Recent studies using dominantnegative forms of α-actinin-2 provide strong evidence that Ca2+-induced rundown of NMDA receptor channel activity is largely the result of breaking the α-actinin-2 link between actin filaments and the receptor itself [18,19]. This finding is further supported by a recent study on cultured neurons showing that latrunculin A, a powerful actin-depolymerizing drug, simultaneously dissociates αactinin-2 from receptor clusters and disperses NMDA receptors away from synaptic sites [20•]. The influence of α-actinin-2 on NMDA receptor function is presumably restricted by α-actinin-2’s limited distribution in the brain; for example, in the hippocampus, its expression is high in area CA2 but extremely low in areas CA1 and CA3 [21]. Elsewhere, other actin-binding proteins may influence NMDA receptor function. Spectrin, a more widely distributed actin-bundling protein, binds NMDA receptors at a site distinct from that used by αactinin-2, and this interaction is also antagonized by Ca2+ [22]. NMDA receptors are also influenced by gelsolin, an actin-binding protein that severs actin filaments in a Ca2+dependent manner. In hippocampal neurons from gelsolin knockout mice, Ca2+ influx through NMDA receptors is increased because the normal channel inactivation that
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results from Ca 2+-induced actin depolymerization is reduced [23]. This increase in Ca2+ influx is probably attributable to the fact that actin filaments are partially protected from Ca2+-induced depolymerization in these gelsolin-deprived cells. AMPA receptors also are sensitive to the assembly state of actin. Like NMDA receptors, they are displaced from synaptic sites when actin filaments are depolymerized, but differences in their patterns of dispersal suggest that the two receptor types are linked to the actin cytoskeleton by distinct mechanisms [20•]. This observation is consistent with recently described differences in their synaptic expression patterns. During postnatal development, most synapses initially display only NMDA receptor activity, with AMPA responses emerging later through an activitydependent mechanism that involves the physical recruitment of AMPA receptor to postsynaptic sites [24,25]. Very recently, it has been shown in brain slices maintained in vitro that tetanic stimulation sufficient to produce NMDA-receptor-dependent long-term potentiation (LTP) of synaptic transmission induces rapid delivery of GFP-labelled AMPA receptors molecules to dendritic spines [26••]. The involvement of actin filaments in these changes in receptor expression is suggested by the effects of directly perfusing actin-depolymerizing drugs into neurons, which produce a decrease in both the magnitude of LTP and in AMPA-receptor-mediated synaptic transmission, without affecting NMDA receptor responses [27]. AMPA receptors appear to remain labile even after synapses are established, as it has been found that AMPA receptors are lost reversibly from synaptic sites within 5 min following their activation, resulting in a transitory 50% decrease in postsynaptic current [28]. AMPA receptor expression is also linked to synaptic morphology. Synapses smaller than 180 nm across have been found to contain only NMDA receptors; above this size, the number of immunohistochemically detectable AMPA receptors increases linearly with synaptic diameter [29]. Increased AMPA receptor numbers are also associated with synapses containing perforated PSDs [30], a feature that has been proposed as a contributory mechanism to activity-induced synaptic plasticity [31,32,33•].
Links to synaptic junctions One molecule that may link AMPA receptors to the actin cytoskeleton is SAP97, one of the large number of synaptic junction proteins with PDZ domains (reviewed in [34]), which binds to the actin cytoskeleton through its amino terminus and to the GluR1 AMPA receptor subunit through its PDZ domain [35•]. SAP97 is also expressed at intercellular junctions in epithelial cells, where it associates with molecular complexes formed between the Ca2+-dependent cell adhesion molecule cadherin and its intracellular partner catenin [36]. Nevertheless, its primary association is with the actin cytoskeleton. Actin/SAP97 adducts form first and are then recruited to focal contact
sites by cadherin/catenin complexes when intercellular junctions are formed [37]. In neurons, cadherin/catenin complexes to which SAP97 binds are located at the borders of active zones, where presynaptic vesicle release sites are in register with postsynaptic neurotransmitter receptors [38]. The linkage of SAP97 to these complexes may be important in determining the structural relationship of AMPA receptors and the actin cytoskeleton in the postsynaptic membrane. Another PDZ domain protein with an intriguing relationship to both actin and AMPA receptors is neurabin (short for neural tissue actin-binding protein), which exists in two forms: neuron-specific neurabin I and the more widely expressed neurabin II/spinophilin [39,40]. Like SAP-97, neurabin has an actin-binding domain at its amino terminus; however, its carboxyl terminus contains coiled-coil domains through which it forms homo-oligomers, allowing it to also function as an actin-bundling protein [40,41]. Through its PDZ domain, neurabin binds to several other proteins, such as protein phosphatase 1 (PP1), whose postsynaptic actions include limiting the rundown of AMPA receptor channel activity. This effect is increased when PP1 binds to neurabin II/spinophilin, presumably because it is then anchored through postsynaptic actin filaments in the vicinity of phosphorylated substrate sites on AMPA receptors [42]. A second neurabin-binding partner is p70 S6 kinase (p70S6K) [43], an enzyme that regulates the translation of a set of abundant mRNAs that contain polypyrimidine tracts in their 5′-untranslated domains [44]. The activity of p70S6K increases substantially when it binds to neurabin [43], suggesting a possible link between the actin cytoskeleton and the control of translational activity in neurons. Anchoring of neurabin–p70S6K complexes to spine-associated actin would place p70S6K close to clusters of polyribosomes present at the bases of dendritic spines that have long been discussed in terms of their possible contribution to local protein synthesis (see [45]).
Morphological plasticity Dynamic imaging of living neurons has revolutionized the study of anatomical plasticity at synapses by making it possible to observe directly the events underlying activity-dependent changes in dendritic spine morphology that previously could only be inferred from examining fixed tissue. A significant early discovery was the motile behaviour of filopodia-like protrusions at the surface of developing dendrites, from which mature dendritic spines develop [46,47]. Two recent studies have extended this observation by showing that stimulation protocols that produce NMDA-receptor-dependent LTP in brain slices can induce the formation of new spine-like structures on dendrites [48••,49••]. Both the motility and relatively rapid appearance of these protrusions suggest that their outgrowth depends on an actin-based mechanism, although this has not yet been demonstrated. These studies did not
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Figure 1 Schematic showing the possible influence of glutamate receptor activation on dendritic spine actin. On the basis of recent data, this diagram summarizes the potential effects of NMDA- and AMPA-type glutamate receptors on the assembly and motility of postsynaptic actin at glutamatergic excitatory synapses. (a) During development, synaptic vesicles in swellings (synaptic boutons) on axons release glutamate, which binds to NMDA receptors on the surfaces of developing dendrites. (b) Actin filaments assemble at these sites and drive the outgrowth of filopodial-like dendritic spine precursors. This depends on strong activation of NMDA recpetors, which can be experimentally induced by high-frequency stimulation protocols that produce LTP of synaptic transmission. This same NMDA-receptor-dependent stimulation induces the acquisition of postsynaptic AMPA receptors. Activation of AMPA receptors by glutamate at levels subthreshold for action potential firing leads to stabilization of motile spines, which then adopt the ‘classical’ round-head morphology. As indicated by the bidirectional arrows, both AMPA-receptor-dependent stabilization of spine morphology and maintenance of spine number appear to be reversible. See text for additional details.
Activity-dependent modification of dendritic spine actin (a) Synaptic vesicle Axon NMDA receptor
An important issue concerns the relationship between these rapid, actin-dependent changes in spine morphology and long-term changes in circuit connectivity. It has long been known that spines that regress when their axonal inputs are cut can subsequently re-emerge when sprouting axons from neighbouring pathways re-innervate vacated postsynaptic sites (see e.g. [51]). This phenomenon has recently been examined in hippocampal slice cultures in which minute lesions produced both a reduction in total spine number and a decline in large mushroom-shaped spines, which were replaced by stubby remnants [52••]. This regression could be mimicked by blocking neurotransmitter release with botulinum toxin, and, conversely, the spine loss produced by lesioning could be avoided by adding low concentrations of AMPA to the cultures, suggesting that low-level AMPA receptor stimulation is both necessary and sufficient for spine maintenance [52••].
Dendrite
Actin
LTP NMDA receptor (b)
show that these newly generated spines make synaptic contacts, although this is likely because nascent spines in brain tissue of equivalent age to the tissue slices used in these studies are contacted by axons [50]. Actin-dependent shape changes in dendritic spines have been demonstrated directly in time-lapse recordings of neurons transfected with GFP-tagged actin [4••]. The spines analysed in this study were shown to be contacted by presynaptic terminals, thus demonstrating that dendritic spines at established synapses retain the capacity for morphological plasticity. An interesting feature of this plasticity is its rapidity: changes in spine shape were detectable between frames taken less than 2 s apart. More recent observations of GFP–actin-expressing neurons in our laboratory have shown that, in contrast to the NMDAreceptor-dependent induction of new spines, actin-based shape changes in spines at established synapses are inhibited by AMPA receptor activation (M Fischer, S Kaech, U Wagner, A Matus, unpublished data).
Glutamate
Filopodia
Subthreshold stimulation AMPA receptor (c)
AMPA receptor Spine
Current Opinion in Neurobiology
Together, these recent experiments suggest a scenario in which spines are initially produced as motile structures in response to NMDA receptor activation and, subsequently, become morphologically stabilized by AMPA-receptormediated transmission (Figure 1).
Conclusions The existence of actin-dependent changes in dendritic spine morphology is now firmly established. The purpose of this cytoskeletal plasticity is almost certainly to adapt circuit connectivity to varying patterns of stimulation, either by modulating transmission efficiency of existing
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synapses or by removing redundant dendritic spines and producing new ones at other sites. In principle, both effects could co-exist as intermediate and extreme states of the same actin-based morphogenic process. The growing evidence for activity-dependent changes in connectivity at glutamatergic synapses in both the developing and the adult brain already point in this direction [53•,54•] and provides good reason for continuing to explore the role of postsynaptic actin.
15. Halpain S, Hipolito A, Saffer L: Regulation of F-actin stability in • dendritic spines by glutamate receptors and calcineurin. J Neurosci 1998, 18:9835-9844. This study implicates actin in early events of excitotoxic neuron damage. The authors report that exposing hippocampal neurons to high concentrations (50 µM) of NMDA caused both loss of synaptic actin and disappearance of dendritic spines within 5 min. The effects were inhibited by blockers of calcineurin, implicating this Ca2+-dependent phosphatase in regulating postynaptic actin. 16. Rosenmund C, Westbrook GL: Calcium-induced actin depolymerization reduces NMDA channel activity. Neuron 1993, 10:805-814. 17.
Acknowledgements The author wishes to acknowledge his debt to Professor EG Gray, who died recently, for introducing him to the concepts of synaptic organization.
References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as:
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