Chemical Synapses

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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

Full Article on Wiley Online Library

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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 active zone (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 (Src‐homology domain 3 (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 metabotropic glutamate receptor (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 calcium/calmodulin‐dependent protein kinase II (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.

Article Title:	Chemical Synapses
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