Development and Regulation of Dendritic Spine Synapses

doi:10.1152/physiol.00042.2005 21:38-47, 2006.Physiology Barbara Calabrese, Margaret S. Wilson and Shelley Halpain Development and Regulation of Dendritic Spine Synapses You might find this additional info useful... 130 articles, 49 of which can be accessed free at:This article cites http://physiologyonline.physiology.org/content/21/1/38.full.html#ref-list-1 7 other HighWire hosted articles, the first 5 are:This article has been cited by [PDF] [Full Text] [Abstract] , December , 2010; 118 (2): 602-612.Toxicol. Sci. Jaime Renau-Piqueras Ana M. Romero, Guillermo Esteban-Pretel, María P. Marín, Xavier Ponsoda, Raúl Ballestín, Juan J. Canales and and Microtubules in Hippocampal Neurons in Primary Culture Chronic Ethanol Exposure Alters the Levels, Assembly, and Cellular Organization of the Actin Cytoskeleton [PDF] [Full Text] [Abstract] , March 2, 2011; 31 (9): 3197-3206.J. Neurosci. Roder and Albert H. C. Wong Frankie H. F. Lee, Marc P. Fadel, Kate Preston-Maher, Sabine P. 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Bonds, Atsushi Miyanohara, Ingrid Neuron-targeted Caveolin-1 Protein Enhances Signaling and Promotes Arborization of Primary Neurons [PDF] [Full Text] [Abstract] , January 1, 2012; 125 (1): 67-80.J Cell Sci Joongkyu Park, Jee Young Sung, Joohyun Park, Woo-Joo Song, Sunghoe Chang and Kwang Chul Chung Dyrk1A negatively regulates the actin cytoskeleton through threonine phosphorylation of N-WASP including high resolution figures, can be found at:Updated information and services http://physiologyonline.physiology.org/content/21/1/38.full.html can be found at:Physiologyabout Additional material and information http://www.the-aps.org/publications/physiol This information is current as of April 3, 2012. Copyright © 2006 by the American Physiological Society. ISSN: 1548-9213, ESSN: 1548-9221. Visit our website at http://www.the-aps.org/. 20814-3991.bimonthly in February, April, June, August, October, and December by the American Physiological Society, 9650 Rockville Pike, Bethesda MD (formerly published as News in Physiological Science) publishes brief review articles on major physiological developments. It is publishedPhysiology o n April 3, 2012 physiologyonline.physiology.org D ow nloaded from organelle called the “spine apparatus” (34). Endocytic machinery is also identified in spines, within special- ized subdomains (88, 102). In addition, polyribosomes and protein translational machinery are often anchored at the base of spines (80). Thus increasing evidence suggests that individual spines represent partially autonomous compartments, having their own regulated membrane-trafficking events that shut- tle components into and out of the spine membrane. Together, these specialized molecular assemblies determine spine shape and, most importantly, enable the postsynaptic neuron to respond biochemically to glutamate or other transmembrane signals (44, 100, 127). Proteomic approaches have begun to unravel the molecular composition of isolated PSD fractions and glutamate receptor complexes and have uncovered a remarkable degree of complexity (48, 83, 116, 124). Although it appears that all spines share several core components, at least some of the apparent molecular complexity probably reflects the fact that individual spine synapses are heterogeneous, exhibiting variable levels of important signaling molecules that can fine- tune individual synaptic responses. Despite advances in our understanding of the molecular composition of spines, their function is not entirely understood. For example, why do some synapses occur on spines and others (“shaft synaps- es”) directly on the dendrite? One widely accepted explanation is that spines provide biochemical com- partmentalization (76). The narrow neck of the spine creates a spatially isolated compartment where bio- chemical signals can rise and fall without spreading to neighboring synapses along the parent dendrite, thus allowing the isolation and/or amplification of incom- ing signals. Similarly, a spine compartment may help confine membrane trafficking to a localized region. Such restriction of molecular signals to one spine may contribute to the phenomenon of “input specificity,” allowing a given set of nerve terminals to induce changes only at those synapses that are specific to their postsynaptic contacts and not at other synapses on the same neuron that are driven by different axons (64). 38 1548-9213/06 8.00 ©2006 Int. Union Physiol. Sci./Am. Physiol. Soc. Dendritic Spines: What Are They? What Are They For? Dendritic spines are micron-sized protrusions of the dendritic membrane that serve as the postsynaptic component for the vast majority of central nervous system excitatory synapses. They are found on excita- tory and inhibitory neurons including glutamatergic pyramidal neurons of the neocortex and hippocampus as well as GABAergic cerebellar Purkinje neurons and medium-sized projection neurons of the striatum. Although their existence has been known for over a century (89), their ultrastructural and molecular organizations have only recently begun to be elucidat- ed due to advances in microscopy and molecular approaches. The number and shape of dendritic spines are varied and highly mutable on time scales ranging from seconds to days, and morphological dif- ferences between spines are known to reflect function- al differences (42). Furthermore, spine numbers and shape are regulated by both physiological and patho- logical events. Most mature spines have a club-like morphology, with variably-shaped bulbous tips, ~0.5–2 �m in diameter, connected to the parent dendrite by thin stalks 0.04–1 �m long (41). Spine density ranges from 1 to 10 spines per micrometer length of dendrite, depending on neuronal cell type and maturational stage. By electron microscopy, the ultrastructure of dendritic spines is characterized by a conspicuous postsynaptic density (PSD). The PSD is a compact matrix that lies just beneath the postsynaptic mem- brane. It organizes the receptors and signaling mole- cules that are positioned across the synaptic cleft from clusters of presynaptic neurotransmitter vesicles (98). The shape and stability/motility of spines are deter- mined by a cytoskeleton composed mostly of filamen- tous actin (F-actin). Spines are nearly completely devoid of the intermediate filaments and micro- tubules that are plentiful in the dendritic shaft (48). Despite their modest size, most spines contain at least some form of smooth endoplasmic reticulum, which in the largest spines takes the form of a specialized REVIEWS Development and Regulation of Dendritic Spine Synapses Barbara Calabrese, Margaret S. Wilson, and Shelley Halpain Department of Cell Biology and Institute for Childhood and Neglected Diseases, The Scripps Research Institute, La Jolla, California shelley@scripps.eduDendritic spines are small protrusions from neuronal dendrites that form the postsy- naptic component of most excitatory synapses in the brain. They play critical roles in synaptic transmission and plasticity. Recent advances in imaging and molecular tech- nologies reveal that spines are complex, dynamic structures that contain a dense array of cytoskeletal, transmembrane, and scaffolding molecules. Several neurologi- cal and psychiatric disorders exhibit dendritic spine abnormalities. PPHHYYSSIIOOLLOOGGYY 2211:: 3388––4477,, 22000066;; 1100..11115522//pphhyyssiiooll..0000004422..22000055 o n April 3, 2012 physiologyonline.physiology.org D ow nloaded from Spine Development During early synaptogenesis, dendritic shafts are cov- ered with filopodia, which are long, narrow protru- sions that are more transient and contain less F-actin than spines. Neuronal growth cones also display numerous filopodia, but these seem to be somehow distinct. Growth cone filopodia are involved in activi- ty-independent dendritic growth and branching, whereas the filopodia that protrude from the dendrite shaft are involved in activity-dependent synaptogene- sis (87). Dendritic filopodia transiently extend and retract from the dendritic shaft with an average life- time of ~10 min (129). Filopodia probably function to maximize the chance encounter between a developing axon and a target dendrite. Once contact is made— either physically via cell-cell adhesions or chemically via locally released signals—a synapse can be initiated and proceed through appropriate maturational steps. Such maturation requires intricate crosstalk between the nascent presynaptic and postsynaptic parts of the synapse (31). As synapse formation progresses over the course of several days, the numerous dendritic filopodia are gradually replaced by spines (67). It appears that many, but not all, spine synapses result when synaps- es initially form on filopodia, which then “convert” directly into spines. However, other synapses form directly on the dendritic shaft, followed by the gradual emergence of spines at the site of contact (24). Laboratory observations suggest that both mecha- nisms can and do occur even within a single neuron (22). It should be noted, however, that not all filopodia are transformed into spines (129). Filopodia are also found on nonspiny neurons during early synaptogen- esis (121). Thus multiple factors, including cell-recog- nition molecules and downstream signals, orchestrate both synapse identity and synapse shape during neu- ronal maturation. Regulation of Spine Development The exquisite molecular organization of the pre- and postsynaptic apparatus requires positional informa- tion to coordinate the correct placement of pre- and postsynaptic elements. Once synapses have appeared, the next steps are to ensure synaptic specificity and to strengthen or weaken synaptic connections (126), processes that are believed to be at the core of learning and memory. The formation of synapses and their neurotransmitter specificity are controlled by the expression of adhesion and signaling molecules, including several classes of neural cell adhesion mole- cule (NCAM), N-cadherins, protocadherins, neurexins with their neuroligins, Eph receptors with their ephrin ligands, and extracellularly secreted molecules like proteoglycans (107, 117). The formation of cell-cell contacts at synapses is similar in basic principles to formation of junctions between nonneuronal cells. However, the polarized, asymmetric nature of pre- and postsynaptic elements confers unique demands on synaptic junctions. Identification of the key signals that establish initial contact is a rapidly growing area of investigation. Much of the remarkable diversity in synaptic function that varies across brain region, neu- ron type, maturational state, and activity level may stem from diversity in the molecules that govern synaptogenesis. Cadherins are a family of calcium-dependent homotypic cell-adhesion molecules (CAMs) that are found in nearly all cells; neurons express an isoform known as N-cadherin (107). As synapses are initiated, N-cadherin begins to cluster on both pre- and postsy- naptic sides of the nascent synapse. This clustering and adhesion is required to establish strong, stable junctions. In older synapses, N-cadherin clusters are mainly concentrated lateral to the PSD (106, 107, 113). To establish strong adhesion, N-cadherins must link to the cytoskeleton by binding to �-catenin, which in turns binds to �-catenin, which binds directly to F- actin. The cadherin/�-catenin complex also bridges to the actin cytoskeleton indirectly via actin-binding pro- teins such as �-actinin or profilin (74). The expression of a dominant-negative truncated N-cadherin, lacking parts of its extracellular domain, leads to massive mor- phological and functional perturbation of spines and synapses in hippocampal neurons (111). These results are supported by studies with �-catenin-deficient neurons that suggested that �-catenin is required for both N-cadherin-mediated adhesion and the shorten- ing of spines and the maturation of synapses (1). Importantly, depolarization-induced redistribution and association of �-catenin with N-cadherin indi- cates an active involvement of �-catenin in N-cad- herin-mediated synaptic adhesion (71). �-Catenin’s phosphorylation state regulates its redistribution between the dendritic spine or the shaft compart- ment: a single point mutation (Y654F) that prevents phosphorylation by a tyrosine kinase concentrates �- catenin in spines, whereas a single point mutation that mimics phosphorylation (Y654E) accumulates �- catenin in dendritic shafts (71). Other catenins known as �-catenins also participate in spine regulation (57). They not only bind to classical cadherins but also interact directly with cortactin in a tyrosine phospho- rylation-dependent manner (65). The protocadherins represent the largest subgroup of the cadherin superfamily, and they display numer- ous splice variants that could potentially encode aspects of synaptic diversity (55). Protocadherin extra- cellular domains exhibit characteristics of calcium- dependent adhesion molecules, but their cytoplasmic domains are different from those of classical cad- herins. The �- and �-protocadherin proteins are enriched in neurons and targeted to synapses (86). Synapse number is reduced in the spinal cord of mice 39PHYSIOLOGY • Volume 21 • February 2006 • www.physiologyonline.org REVIEWS o n April 3, 2012 physiologyonline.physiology.org D ow nloaded from shown that neuroligin splice variants can display dis- tinct neurexin binding preferences and thereby induce distinct effects on synapse formation (9). In addition, association with postsynaptic scaffolding proteins, such as PSD-95, regulates the distribution of NLs and their synaptogenic activity. Whereas NL-2 is usually prevalent at inhibitory synapses, an increase in PSD- 95 levels through overexpression sequesters NL-2 at excitatory postsynaptic sites (114), thereby reducing its distribution to inhibitory synapses. This results in an increased ratio of excitatory to inhibitory synaptic contacts (59, 60). Extracellularly secreted molecules can also influ- ence spine development. Syndecan-2, a heparin sul- fate proteoglycan, was one of the first molecules iden- tified that can trigger spine formation (23). Syndecan- 2 accumulates on spines beginning at the onset of spine formation, and spine-like structures lacking synaptic contacts can be induced when syndecan-2 is overexpressed in neurons before spinogenesis (23). Brain-derived neurotrophic factor or stimulation of its receptor, TrkB, increases Purkinje and hippocampal cell spine density (53, 99). Soluble glia-derived signals are also important in synapse formation and matura- tion. One such signal secreted by astrocytes is choles- terol, which becomes bound to apoE-containing lipoproteins (68). In addition, thrombospondins released by astrocytes have been identified as partici- pating in synaptogenesis (16), and tissue plasminogen activator regulates spine pruning (66). Intracellular components of normal spines can also sometimes trigger formation of spine-like protrusions in neurons that normally lack spines. For example, overexpression of the glutamate receptor 2 (GluR2) subunit of AMPA receptors induces spine formation in GABA-releasing interneurons, which normally lack spines (82). Also, overexpression of Shank, a scaffold- ing molecule that links up to the actin cytoskeleton, can trigger spine formation in such aspiny inhibitory neurons (92), whereas in spiny excitatory neurons, where it is expressed naturally, Shank overexpression induces spine enlargement (94). Such studies demon- strate that certain synaptic molecules can recruit the necessary cytoskeletal and membrane components that enable the postsynaptic membrane to reorganize and protrude into a spine-like structure. Interactions between the membrane-bound ligands ephrins and their tyrosine kinase receptors, Ephs, can also strongly alter spine morphology. Neurons from mice lacking the three receptors EphB1, B2, and B3 fail to form mature spines in vitro, retaining immature filopodia and develop abnormal spines in vivo (43). The binding of ephrin B to EphB triggers various signal transduction pathways involving Rho-family GTPases (see below). In summary, dendritic development and differenti- ation are regulated by a combination of neurotrophin, cell adhesion, and neural and glial activities. However, 40 PHYSIOLOGY • Volume 21 • February 2006 • www.physiologyonline.org lacking protocadherin-� proteins, suggesting that they may be essential for the assembly of certain synapse populations (119). Other candidates for mediating synapse selectivity include several members of the immunoglobulin superfamily of CAMs, which, like the cadherins, work through homotypic association of their extracellular domains to join adjacent cells. CAMs work in concert dynamically together with integrins to mediate and regulate adhesion across the synapse (4, 5, 12). Such immunoglobulin family members include, among others, NCAM, synaptic cell adhesion molecule, and nectin, and these are known in many cases to affect dendritic spine shape and development (see Ref. 117 for review). The neurexin-neuroligin system has received recent attention as a major regulator of synapse and spine formation (95). These molecules work transsynapti- cally in pairs at both glutamatergic and GABAergic synapses, generally with neurexin on the presynaptic side inducing postsynaptic differentiation and neu- roligin on the postsynaptic side inducing presynaptic differentiation (33). One crucial aspect of synapse formation is whether a nascent synapse will develop into an excitatory or inhibitory contact. The tight balance between excita- tory vs. inhibitory synapses regulates the overall excitability of the neuron and is thus critical for nor- mal circuit establishment and firing pattern. The importance of the neuroligin family in this function was demonstrated using RNA interference directed against the neuroligin isoforms NL-1, -2, and -3, which showed that decreased expression of neuroligin resulted in a loss of both excitatory glutamatergic and inhibitory GABAergic synapses in cultured rat hip- pocampal neurons. The loss of glutamatergic synapses was accompanied by a dramatic decrease in dendritic spines. However, the loss of inhibitory synapse func- tion was more predominant, resulting in a shift in the balance of excitability (14). In a complementary study it was shown that �-neurexin expressed on the surface of nonneural cells or attached to synthetic beads was by itself sufficient to induce the formation of postsy- naptic specializations in contacting dendrites (33). Initially it was thought that the localization of NLs, rather than their isoform, was the key determinant of synapse phenotype (59). However, it was recently REVIEWS “...wholesale spine turnover and morphological changes in existing spines are important for establishing and modulating synaptic circuits during development and synap- tic plasticity.” o n April 3, 2012 physiologyonline.physiology.org D ow nloaded from research continues to uncover new and unexpected pathways that affect spine de