Chemical Synapses

Sherri Thiele, University of Toronto at Scarborough, Scarborough, Ontario, Canada
Joanne Nash, University of Toronto at Scarborough, Scarborough, Ontario, Canada

Published online: September 2010

DOI: 10.1002/9780470015902.a0000037.pub2

Abstract

Chemical synapses are among the most elaborate junctions existing between two cells, enabling communication between neurons through chemical neurotransmission within milliseconds. This fast rate of transmission is achieved through three subsynaptic compartments; the presynaptic bouton, the synaptic cleft and the postsynaptic junction. The presynaptic bouton packages neurotransmitters into synaptic vesicles then releases them into the synaptic cleft. Release of synaptic vesicles occurs through several distinct stages, coordinated by a group of specialised proteins. The postsynaptic density (PSD) has evolved into a complex neurotransmitter reception apparatus, which enables the postsynaptic terminal to modulate the downstream response to neurotransmitters. Following activation of receptors on the postsynaptic membrane, neurotransmitters are taken back up into the presynaptic bouton and repackaged into synaptic vesicles (SVs). The synaptic cleft contains proteins that ensure that active zone and PSD remain in proximity. These proteins are also required during synaptogenesis to ensure that the synapse forms properly.

Key Concepts:

  • There are three major structural components that define the synapse: the presynaptic bouton (also known as presynaptic terminal), postsynaptic junction (also known as postsynaptic terminal) and the synaptic cleft.

  • The presynaptic bouton is responsible for packaging neurotransmitters into synaptic vesicles, then releasing their contents into the synaptic cleft in response to calcium influx.

  • Synaptic vesicles are released at a specialised site within the presynaptic bouton known as the active zone.

  • Synaptic vesicles are released by a process known as exocytosis through several distinct steps involving specialised proteins that form a highly interactive and dynamic protein complex at the site of synaptic vesicle release.

  • Interpretation of the presynaptic message takes place at the postsynaptic membrane through transmembrane proteins called receptors.

  • The postsynaptic density is situated adjacent to the postsynaptic membrane within the postsynaptic terminal, juxtaposed to the presynaptic active zone.

  • The postsynaptic density is composed of receptors, scaffolding and adhesion proteins, kinases and phosphatases, as well as cytoskeletal elements, which are linked together to form macromolecular complexes.

  • The postsynaptic density of excitatory synapses is thicker (more pronounced) than the postsynaptic density of inhibitory synapses.

  • The synaptic cleft is a narrow space, approximately 20–30 nm wide situated between the presynaptic and the postsynaptic plasma membranes.

  • The synaptic cleft is composed of proteinaceous and carbohydrate‐rich cell adhesion molecules.

Keywords: postsynaptic density; presynaptic bouton; synaptic cleft; active zone; neurotransmitter; receptor; synaptic vesicle; scaffold proteins; exocytosis

Figure 1.

(a) Schematic diagram of two pyramidal‐like neurons forming a type 1 glutamatergic synapse. The dendrites of these neurons are typically long tapered processes, whereas the single axon has multiple branches and a more uniform width along its length. Axons typically form synapses en passant (in passage) with dendritic segments from many neurons. (b) Schematic diagram of a synapse, showing the three main components: the presynaptic bouton containing synaptic vesicles (SVs), the synaptic cleft containing neurotransmitters released from SVs and the postsynaptic junction where receptors are localised. (c) Electron micrograph of an asymmetrical type 1 spiny synapse. The presynaptic junction (pre) is characterised by the presence of mitochondria (Mito), numerous synaptic vesicles (SV) and an (AZ), where SVs dock, fuse and release neurotransmitter into the cleft. The electron‐dense material associated with the postsynaptic reception apparatus (postsynaptic density; PSD) contains a high concentration of neurotransmitter receptors.
Figure 2.

Schematic diagram of the interacting protein complexes involved in synaptic vesicle cycling and maintenance of the presynaptic active zone. The presynaptic cytoskeletal matrix proteins assembled at the active zone including munc 13/18, piccolo, bassoon, α‐liprin, CASTs/ERCs (CAZ‐associated structural protein/ELKS, Rab6‐interacting protein 2, cast protein family) (ELKS) and rab3‐interacting molecules (RIM), to help define the active zone as the neurotransmitter release site by clustering voltage‐gated calcium channels and the machinery involved in exocytosis and endocytosis, as well as guiding synaptic vesicles in the reserve pool to the docked pool. In docked vesicles, SNAREs and synaptotagmins are not engaged in direct interactions. During priming, SNAp receptor (SNARE) complexes form, complexins (Cpx) are bound to fully assembled complexes, and synaptotagmins constitutively associate with assembled SNARE complexes. The synaptic vesicle membrane and plasma membrane are forced into proximity by SNARE complex assembly, which results in an unstable intermediate. Calcium influx through voltage‐gated calcium channels further destabilises the fusion intermediate by triggering the C2‐domains of the synaptotagmin to partially insert into the phospholipids. This action is proposed to cause a mechanical perturbation that opens the fusion pore. NT, neurotransmitter.
Figure 3.

The postsynaptic density at inhibitory synapses is far less developed compared to excitatory synapses. The scaffold at inhibitory synapses is largely composed of gephyrin, which is believed to oligomerise and form a submembranous hexagonal lattice. Gephyrin offers binding sites for the attachment of the main types of inhibitory receptors, glycine receptors and γ‐aminobutyric acid (GABA) receptors, at synapses. Gephyrin also interacts with the cytoskeleton and adhesion proteins as well as proteins that are involved in trafficking such as the dynein light chain (Dlc) proteins as well as with synaptic regulatory proteins such as proteinase inhibitor 1 (PIN1). PIN1 has been proposed to induce a conformational change of gephyrin and thus control the affinity of the glycine receptor–gephyrin interaction.
Figure 4.

The postsynaptic density at excitatory synapses is a highly complex structure composed of membrane receptors and ion channels, scaffold and adaptor proteins, signalling proteins, cell‐adhesion molecules and components of the cytoskeleton. Glutamate receptors, such as N‐methyl‐d‐aspartate (NMDA) and α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid (AMPA) receptors, are located at the postsynaptic membrane, with NMDA receptors (NMDARs) being localised at the centre with AMPA receptors (AMPARs) being located more peripherally. The PDZ‐domain‐containing scaffold proteins PSD‐95 (postsynaptic density 95) and the shank ( (SH3) and multiple ankyrin repeat domains) family proteins form protein network below the postsynaptic membrane consisting of two layers, which is bridged by guanylate kinase‐associated protein (GKAP). PSD‐95 is situated perpendicular to the membrane as a roughly equally spaced filamentous structure, with its amino terminus attached to the membrane. Interactions between PSD‐95 and AMPARs are mediated by stargazin. PSD‐95 also interacts with Kalirin, which promotes spine formation, and SPAR, a Rap‐specific GTPase‐activating protein that also stimulates spine growth. Shank family scaffolds are further linked to actin filaments through interactions with cortactin and to the (mGluR) and inositol‐1,4,5‐trisphosphate receptor (IP3R) mediated by interactions with homer. Other signalling molecules occupy the spaces in the PSD‐95–GKAP–shank protein such as (CAMKII).
Figure 5.

The synaptic cleft is filled with proteinaceous and carbohydrate‐rich molecules, some of which represent extracellular domains of synaptic membrane‐bound or transmembrane proteins. Cadherins form adhesive bonds between the presynaptic and the postsynaptic membranes through homophilic interactions and localise to the peripheral regions of the synapse. Neuroligins localise postsynaptically and bind to neurexins at the presynaptic membrane early in the developing synapse. Ephrins localise both presynaptically and postsynaptically and with N‐methyl‐d‐aspartate receptors (NMDARs). Both proteins have many splice variants; thus, it has been suggested that this heterophilic interaction regulates synapse formation and perhaps determines the type of synapses that are formed. SynCAM 1 and neuroligins are the only two known proteins that are sufficient to drive formation of presynaptic terminals. Abbreviations: AMPAR, α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid receptor; CASK, calcium/calmodulin‐dependent serine protein kinase; PSD, postsynaptic density; SynCAM 1, synaptic cell adhesion molecule 1.
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References

Baron MK, Boeckers TM, Vaida B et al. (2006) An architectural framework that may lie at the core of the postsynaptic density. Science 311(5760): 531–535.

Bats C, Groc L and Choquet D (2007) The interaction between stargazin and PSD‐95 regulates AMPA receptor surface trafficking. Neuron 53(5): 719–734.

Bedet C, Bruusgaard JC, Vergo S et al. (2006) Regulation of gephyrin assembly and glycine receptor synaptic stability. Journal of Biological Chemistry 281(40): 30046–30056.

Betz A, Okamoto M, Benseler F and Brose N (1997) Direct interaction of the rat unc‐13 homologue Munc13‐1 with the N terminus of syntaxin. Journal of Biological Chemistry 272(4): 2520–2526.

Betz A, Thakur P, Junge HJ et al. (2001) Functional interaction of the active zone proteins Munc13‐1 and RIM1 in synaptic vesicle priming. Neuron 30(1): 183–196.

Blackstone C and Sheng M (2002) Postsynaptic calcium signaling microdomains in neurons. Frontiers in Bioscience 7: d872–d885.

Bogdanov Y, Michels G, Armstrong‐Gold C et al. (2006) Synaptic GABAA receptors are directly recruited from their extrasynaptic counterparts. EMBO Journal 25(18): 4381–4389.

Borgdorff AJ and Choquet D (2002) Regulation of AMPA receptor lateral movements. Nature 417(6889): 649–653.

Brunger AT (2005) Structure and function of SNARE and SNARE‐interacting proteins. Quarterly Reviews of Biophysics 38(1): 1–47.

Chapman ER (2002) Synaptotagmin: a Ca(2+) sensor that triggers exocytosis? Nature Reviews Molecular Cell Biology 3(7): 498–508.

Charrier C, Ehrensperger MV, Dahan M, Levi S and Triller A (2006) Cytoskeleton regulation of glycine receptor number at synapses and diffusion in the plasma membrane. Journal of Neuroscience 26(33): 8502–8511.

DeGiorgis JA, Galbraith JA, Dosemeci A, Chen X and Reese TS (2006) Distribution of the scaffolding proteins PSD‐95, PSD‐93, and SAP97 in isolated PSDs. Brain Cell Biology 35(4–6): 239–250.

Dresbach T, Qualmann B, Kessels MM, Garner CC and Gundelfinger ED (2001) The presynaptic cytomatrix of brain synapses. Cellular and Molecular Life Sciences 58(1): 94–116.

Ehlers MD (2000) Reinsertion or degradation of AMPA receptors determined by activity‐dependent endocytic sorting. Neuron 28(2): 511–525.

Ehlers MD, Heine M, Groc L, Lee MC and Choquet D (2007) Diffusional trapping of GluR1 AMPA receptors by input‐specific synaptic activity. Neuron 54(3): 447–460.

Ehrensperger MV, Hanus C, Vannier C, Triller A and Dahan M (2007) Multiple association states between glycine receptors and gephyrin identified by SPT analysis. Biophysical Journal 92(10): 3706–3718.

Fellin T and Carmignoto G (2004) Neurone‐to‐astrocyte signalling in the brain represents a distinct multifunctional unit. Journal of Physiology 559(part 1): 3–15.

Fenster SD, Chung WJ, Zhai R et al. (2000) Piccolo, a presynaptic zinc finger protein structurally related to bassoon. Neuron 25(1): 203–214

Fenster SD, Kessels MM, Qualmann B et al. (2003) Interactions between piccolo and the actin/dynamin‐binding protein Abp1 link vesicle endocytosis to presynaptic active zones. Journal of Biological Chemistry 278(22): 20268–20277.

Fuhrmann JC, Kins S, Rostaing P et al. (2002) Gephyrin interacts with dynein light chains 1 and 2, components of motor protein complexes. Journal of Neuroscience 22(13): 5393–5402.

Gerber SH, Garcia J, Rizo J and Sudhof TC (2001) An unusual C(2)‐domain in the active‐zone protein piccolo: implications for Ca(2+) regulation of neurotransmitter release. EMBO Journal 20(7): 1605–1619.

Gray NW, Weimer RM, Bureau I and Svoboda K (2006) Rapid redistribution of synaptic PSD‐95 in the neocortex in vivo. PLoS Biology 4(11): e370.

Gundelfinger ED, Kessels MM and Qualmann B (2003) Temporal and spatial coordination of exocytosis and endocytosis. Nature Reviews. Molecular Cell Biology 4(2): 127–139.

Heine M, Groc L, Frischknecht R et al. (2008) Surface mobility of postsynaptic AMPARs tunes synaptic transmission. Science 320(5873): 201–205.

Jahn R and Scheller RH (2006) SNAREs – engines for membrane fusion. Nature Reviews. Molecular Cell Biology 7(9): 631–643.

Jeyifous O, Waites CL, Specht CG et al. (2009) SAP97 and CASK mediate sorting of NMDA receptors through a previously unknown secretory pathway. Nature Neuroscience 12(8): 1011–1019.

Junge HJ, Rhee JS, Jahn O et al. (2004) Calmodulin and Munc13 form a Ca2+ sensor/effector complex that controls short‐term synaptic plasticity. Cell 118(3): 389–401.

Kaufmann N, DeProto J, Ranjan R, Wan H and Van Vactor D (2002) Drosophila liprin‐alpha and the receptor phosphatase Dlar control synapse morphogenesis. Neuron 34(1): 27–38.

Ko J, Na M, Kim S, Lee JR and Kim E (2003) Interaction of the ERC family of RIM‐binding proteins with the liprin‐alpha family of multidomain proteins. Journal of Biological Chemistry 278(43): 42377–42385.

Koch H, Hofmann K and Brose N (2000) Definition of Munc13‐homology‐domains and characterization of a novel ubiquitously expressed Munc13 isoform. Biochemical Journal 349(part 1): 247–253.

Lai K and Lp N (2009) Synapse development and plasticity: roles of ephrin/Eph receptor signaling. Current Opinion in Neurobiology 19(3): 275–283.

Laumonnier F, Bonnet‐Brilhault F, Gomot M et al. (2004) X‐linked mental retardation and autism are associated with a mutation in the NLGN4 gene, a member of the neuroligin family. American Journal of Human Genetics 74(3): 552–557.

Lise MF and El‐Husseini A (2006) The neuroligin and neurexin families: from structure to function at the synapse. Cellular and Molecular Life Sciences 63(16): 1833–1849.

Missler M and Sudhof TC (1998) Neurexins: three genes and 1001 products. Trends in Genetics 14(1): 20–26.

Nakagawa T, Futai K, Lashuel HA et al. (2004) Quaternary structure, protein dynamics, and synaptic function of SAP97 controlled by L27 domain interactions. Neuron 44(3): 453–467.

Reim K, Mansour M, Varoqueaux F et al. (2001) Complexins regulate a late step in Ca2+‐dependent neurotransmitter release. Cell 104(1): 71–81.

Romorini S, Piccoli G, Jiang M et al. (2004) A functional role of postsynaptic density‐95‐guanylate kinase‐associated protein complex in regulating Shank assembly and stability to synapses. Journal of Neuroscience 24(42): 9391–9404.

Saglietti L, Dequidt C, Kamieniarz K et al. (2007) Extracellular interactions between GluR2 and N‐cadherin in spine regulation. Neuron 54(3): 461–477.

Sharma K, Fong DK and Craig AM (2006) Postsynaptic protein mobility in dendritic spines: long‐term regulation by synaptic NMDA receptor activation. Molecular and Cellular Neurosciences 31(4): 702–712.

Shibasaki T, Sunaga Y, Fujimoto K, Kashima Y and Seino S (2004) Interaction of ATP sensor, cAMP sensor, Ca2+ sensor, and voltage‐dependent Ca2+ channel in insulin granule exocytosis. Journal of Biological Chemistry 279(9): 7956–7961.

Sudhof TC (1995) The synaptic vesicle cycle: a cascade of protein‐protein interactions. Nature 375(6533): 645–653.

Sugiyama Y, Kawabata I, Sobue K and Okabe S (2005) Determination of absolute protein numbers in single synapses by a GFP‐based calibration technique. Nature Methods 2(9): 677–684.

Sutton RB, Fasshauer D, Jahn R and Brunger AT (1998) Crystal structure of a SNARE complex involved in synaptic exocytosis at 2.4 A resolution. Nature 395(6700): 347–353.

Sytnyk V, Leshchyns'ka I, Delling M et al. (2002) Neural cell adhesion molecule promotes accumulation of TGN organelles at sites of neuron‐to‐neuron contacts. Journal of Cell Biology 159(4): 649–661.

Takao‐Rikitsu E, Mochida S, Inoue E et al. (2004) Physical and functional interaction of the active zone proteins, CAST, RIM1, and Bassoon, in neurotransmitter release. Journal of Cell Biology 164(2): 301–311.

Tardin C, Cognet L, Bats C, Lounis B and Choquet D (2003) Direct imaging of lateral movements of AMPA receptors inside synapses. EMBO Journal 22(18): 4656–4665.

Tovar KR and Westbrook GL (2002) Mobile NMDA receptors at hippocampal synapses. Neuron 34(2): 255–264.

Valtschanoff JG and Weinberg RJ (2001) Laminar organization of the NMDA receptor complex within the postsynaptic density. Journal of Neuroscience 21(4): 1211–1217.

Yamazaki Y, Kaneko K, Fujii S, Kato H and Ito K (2003) Long‐term potentiation and long‐term depression induced by local application of ATP to hippocampal CA1 neurons of the guinea pig. Hippocampus 13(1): 81–92.

Ziff EB (2007) TARPs and the AMPA receptor trafficking paradox. Neuron 53(5): 627–633.

Further Reading

Abbas L (2003) Synapse formation: let's stick together. Current Biology 13(1): R25–R27.

Bramham CR (2008) Local protein synthesis, actin dynamics, and LTP consolidation. Current Opinion in Neurobiology 18(5): 524–531.

Craig AM and Kang Y (2007) Neurexin‐neuroligin signaling in synapse development. Current Opinion in Neurobiology 17(1): 43–52.

Feng W and Zhang M (2009) Organization and dynamics of PDZ‐domain‐related supramodules in the postsynaptic density. Nature Reviews. Neuroscience 10(2): 87–99.

Gardoni F, Marcello E and Di Luca M (2009) Postsynaptic density‐membrane associated guanylate kinase proteins (PSD‐MAGUKs) and their role in CNS disorders. Neuroscience 158(1): 324–333.

Hokfelt T (2010) Looking at neurotransmitters in the microscope. Progress in Neurobiology 90(2): 101–118.

Margeta MA and Shen K (2010) Molecular mechanisms of synaptic specificity. Molecular and Cellular Neurosciences 43(3): 261–267.

Opazo F and Rizzoli SO (2010) Studying synaptic vesicle pools using photoconversion of styryl dyes. Journal of Visualized Experiments (36). Available at http://www.jove.com/index/Details.stp?ID=1790

Shupliakov O and Brodin L (2010) Recent insights into the building and cycling of synaptic vesicles. Experimental Cell Research 316(8): 1344–1350.

Specht CG and Triller A (2008) The dynamics of synaptic scaffolds. Bioessays 30(11–12): 1062–1074.

Related Sub-Topics:

Cell Membranes | Synaptic Transmission | Receptors for Neurotransmitters | Intracellular and Extracellular Signalling | Neurotransmitters
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Article Title: Chemical Synapses
 
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Thiele, Sherri, and Nash, Joanne(Sep 2010) Chemical Synapses. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000037.pub2]