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• W2068742937 abstract "Classical physiological work by Katz, Eccles, and others revealed the central importance of synapses in brain function, and characterized the mechanisms involved in synaptic transmission. Building on this work, major advances in the past two decades have elucidated how synapses work molecularly. In the present perspective, we provide a short description of our personal view of these advances, suggest a series of important future questions about synapses, and discuss ideas about how best to achieve further progress in the field. Classical physiological work by Katz, Eccles, and others revealed the central importance of synapses in brain function, and characterized the mechanisms involved in synaptic transmission. Building on this work, major advances in the past two decades have elucidated how synapses work molecularly. In the present perspective, we provide a short description of our personal view of these advances, suggest a series of important future questions about synapses, and discuss ideas about how best to achieve further progress in the field. Enormous progress has been made in recent decades in our understanding of synaptic transmission and its use-dependent plasticity. The development of new tools, in particular in molecular genetics, structural biology, electrophysiology, and imaging has led to a detailed understanding of key phenomena, such as the Ca2+-triggering of neurotransmitter release and some of the key mechanisms underlying synaptic plasticity. Nevertheless, major technical and intellectual challenges remain. As Neuron turns 20, it seems an appropriate time to provide a brief, highly personal perspective on some of the major advances in our understanding of synaptic function over the last two decades, as well as attempt to point out some of the most important future challenges in an area of research that will continue to be critical for understanding both normal and pathological brain function. The last two decades were revolutionary in neuroscience. Years of extraordinary growth and opportunity were provided by expanding technologies, increases in funding, and the realization that understanding the brain is a major, maybe even the most important, frontier in biology. When considering advances in our understanding of synaptic function, much deserves to be noted. However, for reasons of space, we provide a limited list of achievements that reflects our personal bias. This list is thematically organized and not ordered according to perceived importance. Figure 1 provides a schematic illustration of the synapse that highlights some of the points made on the list. Chronologically, the description of the molecular composition of synapses was the first major step toward understanding the basis of synaptic transmission beyond the elegant electrophysiological studies of pioneers such as Fatt, Katz, Llinas, and Eccles. It is hard to remember now how revolutionary the cloning of the Torpedo nicotinic receptor by Numa was (Noda et al., 1982Noda M. Takahashi H. Tanabe T. Toyosato M. Furutani Y. Hirose T. Asai M. Inayama S. Miyata T. Numa S. Primary structure of alpha-subunit precursor of Torpedo californica acetylcholine receptor deduced from cDNA sequence.Nature. 1982; 299: 793-797Crossref PubMed Scopus (489) Google Scholar). This work initiated a 15 year period during which most of the principal components of synapses were purified and cloned. This period started with channels and receptors (e.g., Noda et al., 1982Noda M. Takahashi H. Tanabe T. Toyosato M. Furutani Y. Hirose T. Asai M. Inayama S. Miyata T. Numa S. Primary structure of alpha-subunit precursor of Torpedo californica acetylcholine receptor deduced from cDNA sequence.Nature. 1982; 299: 793-797Crossref PubMed Scopus (489) Google Scholar, Noda et al., 1986Noda M. Ikeda T. Kayano T. Suzuki H. Takeshima H. Kurasaki M. Takahashi H. Numa S. Existence of distinct sodium channel messenger RNAs in rat brain.Nature. 1986; 320: 188-192Crossref PubMed Scopus (679) Google Scholar, Tanabe et al., 1987Tanabe T. Takeshima H. Mikami A. Flockerzi V. Takahashi H. Kangawa K. Kojima M. Matsuo H. Hirose T. Numa S. Primary structure of the receptor for calcium channel blockers from skeletal muscle.Nature. 1987; 328: 313-318Crossref PubMed Scopus (931) Google Scholar, Snutch et al., 1990Snutch T.P. Leonard J.P. Gilbert M.M. Lester H.A. Davidson N. Rat brain expresses a heterogeneous family of calcium channels.Proc. Natl. Acad. Sci. USA. 1990; 87: 3391-3395Crossref PubMed Scopus (216) Google Scholar), continued with synaptic vesicle proteins (the first of which was cloned a year before Neuron was launched [Südhof et al., 1987Südhof T.C. Lottspeich F. Greengard P. Mehl E. Jahn R. Synaptophysin: A synaptic vesicle protein with four transmembrane regions and a novel cytoplasmic domain.Science. 1987; 238: 1142-1144Crossref PubMed Scopus (239) Google Scholar]), and was completed with the cloning of synaptic cell-adhesion molecules, active zone proteins, and proteins of the postsynaptic density (e.g., Cho et al., 1992Cho K.O. Hunt C.A. Kennedy M.B. The rat brain postsynaptic density fraction contains a homolog of the Drosophila discs-large tumor suppressor protein.Neuron. 1992; 5: 929-942Abstract Full Text PDF Scopus (972) Google Scholar, Brose et al., 1995Brose N. Hofmann K. Hata Y. Südhof T.C. Mammalian homologues of C. elegans unc-13 gene define novel family of C2-domain proteins.J. Biol. Chem. 1995; 270: 25273-25280Crossref PubMed Scopus (308) Google Scholar, Ushkaryov et al., 1992Ushkaryov Y.A. Petrenko A.G. Geppert M. Südhof T.C. Neurexins: Synaptic cell surface proteins related to the α-latrotoxin receptor and laminin.Science. 1992; 257: 50-56Crossref PubMed Scopus (523) Google Scholar, Ichtchenko et al., 1995Ichtchenko K. Hata Y. Nguyen T. Ullrich B. Missler M. Moomaw C. Südhof T.C. Neuroligin 1: A splice-site specific ligand for β-neurexins.Cell. 1995; 81: 435-443Abstract Full Text PDF PubMed Scopus (543) Google Scholar). Although the molecular cataloging of synaptic proteins can be viewed as merely descriptive, this work is a prerequisite for understanding synapses. This effort culminated in the systematic analysis of the synaptic vesicle as an organelle (Burré et al., 2006Burré J. Beckhaus T. Schägger H. Corvey C. Hofmann S. Karas M. Zimmermann H. Volknandt W. Analysis of the synaptic vesicle proteome using three gel-based protein separation techniques.Proteomics. 2006; 6: 6250-6262Crossref PubMed Scopus (83) Google Scholar, Takamori et al., 2006Takamori S. Holt M. Stenius K. Lemke E.A. Grønborg M. Riedel D. Urlaub H. Schenck S. Brügger B. Ringler P. et al.Molecular anatomy of a trafficking organelle.Cell. 2006; 127: 831-846Abstract Full Text Full Text PDF PubMed Scopus (1523) Google Scholar), and the development of models for the molecular organization of the presynaptic active zone and the postsynaptic density (Südhof, 2004Südhof T.C. The synaptic vesicle cycle.Annu. Rev. Neurosci. 2004; 27: 509-547Crossref PubMed Scopus (1772) Google Scholar, Kim and Sheng, 2004Kim E. Sheng M. PDZ domain proteins of synapses.Nat. Rev. Neurosci. 2004; 5: 771-781Crossref PubMed Scopus (1142) Google Scholar, Scannevin and Huganir, 2000Scannevin R.H. Huganir R.L. Postsynaptic organization and regulation of excitatory synapses.Nat. Rev. Neurosci. 2000; 1: 133-141Crossref PubMed Scopus (381) Google Scholar, Schoch and Gundelfinger, 2006Schoch S. Gundelfinger E.D. Molecular organization of the presynaptic active zone.Cell Tissue Res. 2006; 326: 379-391Crossref PubMed Scopus (230) Google Scholar). Much, however, remains unknown, including a complete list of synaptic cell-adhesion molecules and a detailed understanding of the stoichiometric composition of proteins at different types of synapses. Presynaptic neurotransmitter release is mediated by the Ca2+-triggered fusion of synaptic vesicles with the presynaptic plasma membrane at the active zone (Figure 1). The last 20 years achieved a nearly complete understanding of this process. The description of the synaptic vesicle fusion machine, starting with the identification of synaptobrevin/VAMP as the target of tetanus toxin that is responsible for mediating fusion (Schiavo et al., 1992Schiavo G. Benfenati F. Poulain B. Rossetto O. Polverino de Laureto P. DasGupta B.R. Montecucco C. Tetanus and botulinum-B neurotoxins block neurotransmitter release by proteolytic cleavage of synaptobrevin.Nature. 1992; 359: 832-835Crossref PubMed Scopus (1370) Google Scholar, Link et al., 1992Link E. Edelmann L. Chow J.H. Binz T. Yamasaki S. Eisel U. Baumert M. Südhof T.C. Niemann H. Jahn R. Tetanus toxin action: Inhibition of neurotransmitter release linked to synaptobrevin poteolysis.Biochem. Biophys. Res. Commun. 1992; 189: 1017-1023Crossref PubMed Scopus (245) Google Scholar), not only accounted for how synaptic vesicles fuse, but also provided a blueprint for all intracellular fusion reactions (Jahn and Scheller, 2006Jahn R. Scheller R.H. SNAREs--engines for membrane fusion.Nat. Rev. Mol. Cell Biol. 2006; 7: 631-643Crossref PubMed Scopus (1734) Google Scholar). The general principles that apply to all fusion reactions in a cell are simple: a machinery consisting of three or four SNARE proteins and one sec1-Munc18-like protein (SM protein) is positioned and controlled by ancillary proteins, which in the case of the synapse, include active zone proteins such as Munc13 and soluble proteins such as tomosyn (Südhof, 2004Südhof T.C. The synaptic vesicle cycle.Annu. Rev. Neurosci. 2004; 27: 509-547Crossref PubMed Scopus (1772) Google Scholar). In parallel, the discovery of synaptotagmin as the synaptic Ca2+ sensor that is responsible for the majority of release under normal stimulation conditions in all synapses (Perin et al., 1990Perin M.S. Fried V.A. Mignery G.A. Jahn R. Südhof T.C. Phospholipid binding by a synaptic vesicle protein homologous to the regulatory region of protein kinase C.Nature. 1990; 345: 260-263Crossref PubMed Scopus (635) Google Scholar) provided a molecular explanation for Katz's pioneering observation that neurotransmitter release is Ca2+ triggered (Katz, 1969Katz B. The Release of Neural Transmitter Substances. Liverpool University Press, Liverpool1969Google Scholar). This discovery was complemented by the more recent identification of complexin as a cofactor for synaptotagmin in the Ca2+ triggering of release (McMahon et al., 1995McMahon H.T. Missler M. Li C. Südhof T.C. Complexins: cytosolic proteins that regulate SNAP-receptor function.Cell. 1995; 83: 111-119Abstract Full Text PDF PubMed Scopus (359) Google Scholar). A model emerged wherein complexin activates and clamps fusion of synaptic vesicles by binding to partially or fully assembled SNARE complexes (Tang et al., 2006Tang J. Maximov A. Shin O.-H. Dai H. Rizo J. Südhof T.C. A Complexin/Synaptotagmin-1 Switch Controls Fast Synaptic Vesicle Exocytosis.Cell. 2006; 126: 1175-1187Abstract Full Text Full Text PDF PubMed Scopus (324) Google Scholar). Ca2+ entering the terminal during an action potential then binds to synaptotagmin, thereby inducing the simultaneous interaction of synaptotagmin with phospholipids in the membranes and with the SNARE complex. This interaction displaces complexin from the SNARE complex, bends the phospholipids, and opens the fusion pore (Tang et al., 2006Tang J. Maximov A. Shin O.-H. Dai H. Rizo J. Südhof T.C. A Complexin/Synaptotagmin-1 Switch Controls Fast Synaptic Vesicle Exocytosis.Cell. 2006; 126: 1175-1187Abstract Full Text Full Text PDF PubMed Scopus (324) Google Scholar). Many details remain to be clarified in this model; for example, how different synaptotagmin isoforms confer distinct Ca2+ affinities and reaction speeds onto fusion (Xu et al., 2007Xu J. Mashimo T. Südhof T.C. Synaptotagmin-1, -2, and -9: Ca2+-sensors for fast release that specify distinct presynaptic properties in subsets of neurons.Neuron. 2007; 54: 567-581Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar), and whether this diversity is physiologically important. But the fundamental molecular reactions that have been defined are likely to occur in similar fashions in all fast Ca2+-triggered fusion, and account for most of the neurotransmitter, neuropeptide, and hormone secretion observed physiologically. Synapses exhibit marked use-dependent plasticity that manifests as short- and long-term increases or decreases in synaptic strength. Over the last two decades, intense efforts were focused on understanding the mechanisms of NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) and long-term depression (LTD). These efforts were richly rewarded by major discoveries (Lisman et al., 2007Lisman J.E. Raghavachari S. Tsien R.W. The sequence of events that underlie quantal transmission at central glutamatergic synapses.Nat. Rev. Neurosci. 2007; 8: 597-609Crossref PubMed Scopus (168) Google Scholar). A vigorous debate about presynaptic versus postsynaptic expression mechanisms (Malenka and Nicoll, 1999Malenka R.C. Nicoll R.A. Long-term potentiation–a decade of progress?.Science. 1999; 285: 1870-1874Crossref PubMed Scopus (2163) Google Scholar) led to the resolution that NMDAR-dependent forms of LTP and LTD are both mediated primarily by changes in the number of AMPA receptors (AMPARs) in the postsynaptic density (Shepherd and Huganir, 2007Shepherd J.D. Huganir R.L. The cell biology of synaptic plasticity: AMPA receptor trafficking.Annu. Rev. Cell Dev. Biol. 2007; 23: 613-643Crossref PubMed Scopus (706) Google Scholar). Depending on the pattern of synaptic activity and the quantitative properties of the resulting NMDAR-mediated rise in Ca2+ within dendritic spines, AMPARs can undergo either endocytosis during LTD or insertion into the postsynaptic density during LTP (Figure 1). Much has been learned about the molecular details underlying AMPAR trafficking, such as, for example, the importance of the AMPAR accessory proteins TARPs and scaffolding proteins such as PSD-95 (Chen et al., 2000Chen L. Chetkovich D.M. Petralia R.S. Sweeney N.T. Kawasaki Y. Wenthold R.J. Bredt D.S. Nicoll R.A. Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms.Nature. 2000; 408: 936-943Crossref PubMed Scopus (9) Google Scholar, Bredt and Nicoll, 2003Bredt D.S. Nicoll R.A. AMPA receptor trafficking at excitatory synapses.Neuron. 2003; 40: 361-379Abstract Full Text Full Text PDF PubMed Scopus (888) Google Scholar). However, as sophisticated molecular, imaging, and electrophysiological tools are applied to the study of LTP and LTD, it is apparent that the complexity of the functional roles of even a single protein, such as PSD-95, in these phenomena is daunting (Steiner et al., 2008Steiner P. Higley M.J. Xu W. Czervionke B.L. Malenka R.C. Sabatini B.L. Destablization of the postsynaptic density by PSD-95 serine 73 phosphorylation inhibits spine growth and synaptic plasticity.Neuron. 2008; 60 (in press)Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar, Xu et al., 2008Xu W. Schluter O.M. Steiner P. Czervionke B.L. Sabatini B. Malenka R.C. Molecular Dissociation of the Role of PSD-95 in Regulating Synaptic Strength and LTD.Neuron. 2008; 57: 248-262Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar). Although neurons were known to be functionally and structurally polarized even before Ramon y Cajal provided his beautiful drawings, nobody anticipated the powerful capabilities embodied in dendrites. Studies over the last decades uncovered that dendrites, as the postsynaptic compartment par excellence, can do almost everything the neuronal cell body does, but in a more sophisticated, spatially and temporally compartmentalized manner. Dendrites, or rather various dendritic segments, function as autonomous units replete with signaling elements. We now know that dendrites express a complex array of voltage-dependent conductances, allowing them to generate back- and forward-propagating action potentials. They also contain a full-fledged protein synthesis machinery, including a rough endoplasmic reticulum and a functional Golgi complex (Ehlers, 2007Ehlers M.D. Secrets of the secretory pathway in dendrite growth.Neuron. 2007; 55: 686-689Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar) that are likely critical for the local control of the postsynaptic composition of individual synapses. Dendritic spines, the reception points for most excitatory synapses, are compartmentalized extensions of the dendrites that contain a subset of these elements, and serve as entry points to dendritic signaling. As a result of these properties, dendrites integrate synaptic signals in a nonlinear manner (Bourne and Harris, 2008Bourne J.N. Harris K.M. Balancing structure and function at hippocampal dendritic spines.Annu. Rev. Neurosci. 2008; 31: 47-67Crossref PubMed Scopus (626) Google Scholar, Higley and Sabatini, 2008Higley M.J. Sabatini B.L. Calcium signaling in dendrites and spines: practical and functional considerations.Neuron. 2008; 59: 902-913Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar). Many candidate retrograde messengers that might function to carry a postsynaptic signal to presynaptic terminals were advanced over the last decades. However, no consensus molecule emerged until the demonstration that endocannabinoids mediate a phenomenon called depolarization-induced suppression of inhibition (DSI) (Wilson and Nicoll, 2002Wilson R.I. Nicoll R.A. Endocannabinoid signaling in the brain.Science. 2002; 296: 678-682Crossref PubMed Scopus (988) Google Scholar). During DSI, depolarization of a postsynaptic neuron causes transient suppression of GABA release from presynaptic inhibitory terminals contacting this neuron; this suppression is effected by endocannabinoids that act retrogradely (Figure 1). This seminal finding spawned the discovery of a role for endocannbinoids in several additional forms of postsynaptically induced, but presynaptically expressed, plasticity, especially in long-term plasticity of both inhibitory and excitatory synaptic transmission in various brain structures (Chevaleyre et al., 2006Chevaleyre V. Takahashi K.A. Castillo P.E. Endocannabinoid-mediated synaptic plasticity in the CNS.Ann. Rev. Neurosci. 2006; 29: 37-76Crossref PubMed Scopus (592) Google Scholar). Strikingly, whereas short-term endocannabinoid-dependent plasticity is independent of the active zone protein RIM1α, long-term endocannabinoid-dependent presynaptic plasticity requires this protein (Chevaleyre et al., 2007Chevaleyre V. Heifets B.D. Kaeser P.S. Südhof T.C. Castillo P.E. Endocannabinoid-mediated long-term plasticity requires cAMP/PKA signaling and RIM1α.Neuron. 2007; 54: 801-812Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar, Fourcaudot et al., 2008Fourcaudot E. Gambino F. Humeau Y. Casassus G. Shaban H. Poulain B. Lüthi A. cAMP/PKA signaling and RIM1alpha mediate presynaptic LTP in the lateral amygdala.Proc. Natl. Acad. Sci. USA. 2008; 39: 15130-15135Crossref Scopus (74) Google Scholar). Recent results revealed the importance of inhibitory synapses in neural circuits, in addition to the traditionally studied excitatory synapses, beyond what was envisioned earlier. Although fewer inhibitory neurons and synapses are present in brain, inhibitory neurons manifest in a bewildering diversity, and their synapses exert a profound influence on the properties of neural circuits (e.g., see Klausberger and Somogyi, 2008Klausberger T. Somogyi P. Neuronal diversity and temporal dynamics: the unity of hippocampal circuit operations.Science. 2008; 321: 53-57Crossref PubMed Scopus (1287) Google Scholar). The diversity of inhibitory neurons is not only apparent in their shape and connectivity pattern, but also in the properties of their synapses which, among others, can express multiple forms of LTP and LTD (e.g., see Nugent et al., 2007Nugent F.S. Penick E.C. Kauer J.A. Opioids block long-term potentiation of inhibitory synapses.Nature. 2007; 446: 1086-1090Crossref PubMed Scopus (239) Google Scholar), besides the endocannabinoid-dependent forms described above (Chevaleyre et al., 2006Chevaleyre V. Takahashi K.A. Castillo P.E. Endocannabinoid-mediated synaptic plasticity in the CNS.Ann. Rev. Neurosci. 2006; 29: 37-76Crossref PubMed Scopus (592) Google Scholar). Moreover, excitatory synapses on GABAergic interneurons are dynamic and also exhibit a suprisingly diverse repertoire of plasticity (Kullmann and Lamsa, 2007Kullmann D.M. Lamsa K.P. Long-term synaptic plasticity in hippocampal interneurons.Nat. Rev. Neurosci. 2007; 8: 687-699Crossref PubMed Scopus (212) Google Scholar). Neurons are largely irreplaceable after development, apart from a small population of continuously replenished neurons that originate throughout life from the dentate gyrus and subventricular zone (Zhao et al., 2008Zhao C. Deng W. Gage F.H. Mechanisms and functional implications of adult neurogenesis.Cell. 2008; 132: 645-660Abstract Full Text Full Text PDF PubMed Scopus (2278) Google Scholar). The question of whether synapses are similarly irreplaceable, or can be continuously remodeled during the lifetime of an organism, has been difficult to address. The advent of new imaging tools over the last decade revealed that dendritic spines are very dynamic (Lendvai et al., 2000Lendvai B. Stern E.A. Chen B. Svoboda K. Experience-dependent plasticity of dendritic spines in the developing rat barrel cortex in vivo.Nature. 2000; 404: 876-881Crossref PubMed Scopus (603) Google Scholar, Zuo et al., 2005Zuo Y. Yang G. Kwon E. Gan W.B. Long-term sensory deprivation prevents dendritic spine loss in primary somatosensory cortex.Nature. 2005; 436: 261-265Crossref PubMed Scopus (336) Google Scholar). Long-term in vivo imaging experiments suggested that synapses are continuously formed, eliminated, and remodeled throughout adulthood, although the extent of such processes may vary between different brain regions (Grutzendler et al., 2002Grutzendler J. Kasthuri N. Gan W.B. Long-term dendritic spine stability in the adult cortex.Nature. 2002; 420: 812-816Crossref PubMed Scopus (891) Google Scholar, Trachtenberg et al., 2002Trachtenberg J.T. Chen B.E. Knott G.W. Feng G. Sanes J.R. Welker E. Svoboda K. Long-term in vivo imaging of experience-dependent synaptic plasticity in adult cortex.Nature. 2002; 420: 788-794Crossref PubMed Scopus (1401) Google Scholar). Such activity-dependent structural changes in synaptic connectivity likely underlie many forms of experience-dependent plasticity, including learning and memory. Major technical advances that went far beyond classical approaches enabled analysis of the exquisite details of synaptic transmission. Such advances included application of capacitance measurements to directly monitor exocytosis from presynaptic terminals, and the use of caged Ca2+ that can be released by photolysis (Neher and Marty, 1982Neher E. Marty A. Discrete changes of cell membrane capacitance observed under conditions of enhanced secretion in bovine adrenal chromaffin cells.Proc. Natl. Acad. Sci. USA. 1982; 79: 6712-6716Crossref PubMed Scopus (769) Google Scholar, Delaney and Zucker, 1990Delaney K.R. Zucker R.S. Calcium released by photolysis of DM-nitrophen stimulates transmitter release at squid giant synapse.J. Physiol. 1990; 426: 473-498PubMed Google Scholar). Imaging techniques using styryl dyes such as FM1-43, and genetically encoded fluorescent proteins such as synaptophluorin, allowed direct visualization of synaptic vesicle release and cycling (Rizzoli and Betz, 2005Rizzoli S.O. Betz W.J. Synaptic vesicle pools.Nat. Rev. Neurosci. 2005; 6: 57-69Crossref PubMed Scopus (599) Google Scholar). Furthermore, multiphoton microscopy allowed direct visualization and activation of single dendritic spines within intact brain tissue (Mainen et al., 1999Mainen Z.F. Malinow R. Svoboda K. Synaptic calcium transients in single spines indicate that NMDA receptors are not saturated.Nature. 1999; 399: 151-155Crossref PubMed Scopus (254) Google Scholar, Matsuzaki et al., 2004Matsuzaki M. Honkura N. Ellis-Davies G.C. Kasai H. Structural basis of long-term potentiation in single dendritic spines.Nature. 2004; 429: 761-766Crossref PubMed Scopus (1666) Google Scholar). These state-of-the-art approaches have made it possible to answer more and more sophisticated questions about synaptic function. Among the major observations emerging from such studies are a more precise definition of presynaptic exocytosis and postsynaptic signaling, the observation of multivesicular release in an active zone, the exact measurements of presynaptic and postsynaptic Ca2+ concentrations during synaptic transmission (with some caveats about spatial heterogeneity), and the monitoring of individual vesicles during exocytosis and endocytosis (Wadiche and Jahr, 2001Wadiche J.I. Jahr C.E. Multivesicular release at climbing fiber-Purkinje cell synapses.Neuron. 2001; 32: 301-313Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar, Murthy and Stevens, 1998Murthy V.N. Stevens C.F. Synaptic vesicles retain their identity through the endocytic cycle.Nature. 1998; 392: 497-501Crossref PubMed Scopus (221) Google Scholar, Rozov et al., 2001Rozov A. Burnashev N. Sakmann B. Neher E. Transmitter release modulation by intracellular Ca2+ buffers in facilitating and depressing nerve terminals of pyramidal cells in layer 2/3 of the rat neocortex indicates a target cell-specific difference in presynaptic calcium dynamics.J. Physiol. 2001; 531: 807-826Crossref PubMed Scopus (292) Google Scholar, Schneggenburger and Neher, 2000Schneggenburger R. Neher E. Intracellular calcium dependence of transmitter release rates at a fast central synapse.Nature. 2000; 406: 889-893Crossref PubMed Scopus (543) Google Scholar, Bollmann et al., 2000Bollmann J.H. Sakmann B. Borst J.G. Calcium sensitivity of glutamate release in a calyx-type terminal.Science. 2000; 289: 953-957Crossref PubMed Scopus (380) Google Scholar, Sun and Wu, 2001Sun J.Y. Wu L.G. Fast kinetics of exocytosis revealed by simultaneous measurements of presynaptic capacitance and postsynaptic currents at a central synapse.Neuron. 2001; 30: 171-182Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar, Sun et al., 2007Sun J. Pang Z.P. Qin D. Fahim A.T. Adachi R. Südhof T.C. A Dual Ca2+-Sensor Model for Neurotransmitter Release in a Central Synapse.Nature. 2007; 450: 676-682Crossref PubMed Scopus (253) Google Scholar). We believe there are two types of challenges for research on synaptic function over the next decades: to organize our research efforts in the scientific community effectively, and to use these efforts to answer salient questions about synapses that have the biggest chance of providing new insights. From our personal perspective, the following questions about synapses are particularly important. Synapses are diverse in shape and properties. We do not know much about how this diversity is determined, nor what it means for the neural networks in which these synapses participate. What determines the receptor composition of individual synapses? How does a synapse become facilitating or depressing during stimulus trains, and what are the molecular underpinnings for this physiological difference? This property is probably related to synaptic cell adhesion since postsynaptic neurons appear to be instructive for presynaptic properties, and vice versa (Maccaferri et al., 1998Maccaferri G. Toth K. McBain C.J. Target–specific expression of presynaptic mossy fiber plasticity.Science. 1998; 279: 1368-1370Crossref PubMed Scopus (179) Google Scholar, Takamori et al., 2000Takamori S. Rhee J.S. Rosenmund C. Jahn R. Identification of a vesicular glutamate transporter that defines a glutamatergic phenotype in neurons.Nature. 2000; 407: 189-194Crossref PubMed Scopus (686) Google Scholar, Rozov et al., 2001Rozov A. Burnashev N. Sakmann B. Neher E. Transmitter release modulation by intracellular Ca2+ buffers in facilitating and depressing nerve terminals of pyramidal cells in layer 2/3 of the rat neocortex indicates a target cell-specific difference in presynaptic calcium dynamics.J. Physiol. 2001; 531: 807-826Crossref PubMed Scopus (292) Google Scholar), but no molecular mechanisms are known. Identification of the nature and mechanisms that mediate such synapse specification will be important for understanding how neural circuits develop. While evidence has accumulated that the acquisition of new declarative memories involves long-term synaptic plasticity in the hippocampus, little is known about how they are stored long-term in the cortex. Synaptic changes are likely required for memory formation, as is gene transcription, which may be regulated via epigenetic mechanisms during memory formation and may primarily affect “synaptic” genes (Barrett and Wood, 2008Barrett R.M. Wood M.A. Beyond transcription factors: the role of chromatin modifying enzymes in regulating transcription required for memory.Learn. Mem. 2008; 15: 460-467Crossref PubMed Scopus (200) Google Scholar). At least two principal mechanisms are possible by which synaptic mechanisms might store memories: (1) the remodeling of the synaptic wiring diagram by the formation of new synapses and/or the elimination of old synapses, or (2) the selective strengthening and weakening of subsets of synapses without changes in synaptic connectivity. Moreover, memory formation may involve more than synaptic changes, as adult neurogenesis has been hypothesized to be necessary (Leuner et al., 2006Leuner B. Gould E. Shors T.J. Is there a link between adult neurogenesis and learning?.Hippocampus. 2006; 16: 216-224Crossref PubMed Scopus (445) Google Scholar). Addressing the role of synapses in learning and memory requires a better understanding of their dynamics, further insights into the connection between the synapse and the nucleus, and better control of the properties of synaps" @default.
• W2068742937 created "2016-06-24" @default.
• W2068742937 creator A5041585906 @default.
• W2068742937 creator A5061921730 @default.
• W2068742937 date "2008-11-01" @default.
• W2068742937 modified "2023-10-13" @default.
• W2068742937 title "Understanding Synapses: Past, Present, and Future" @default.
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• W2068742937 doi "https://doi.org/10.1016/j.neuron.2008.10.011" @default.
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