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Molecular Structure and Function of Synapses
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Molecular Structure and Function of Synapses

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biophysics".

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 17100

Special Issue Editor

Prof. Dr. Carolin Wichmann

E-Mail Website1 Website2
Guest Editor
Molecular Architecture of Synapses Group, Center for Biostructural Imaging of Neurodegeneration (BIN), Institute for Auditory Neuroscience & InnerEarLab, University Medical Center Goettingen, Von-Siebold-Str. 3a, D-37075 Goettingen, Germany
Interests: ultrastructure of synapses; structure–function; neuroscience; hearing

Special Issue Information

Dear Colleagues,

The mammalian brain harbors billions of neurons, which communicate via chemical synapses. Recent studies have shown that synapses exhibit complex proteomes, with each brain region containing distinct synapse subtypes. Moreover, synapses show different structural features that likely determine functional properties. The presynaptic active zone accumulates numerous proteins to orchestrate neurotransmitter release, including structural proteins such as bassoon and piccolo, proteins involved in synaptic vesicle recruitment, priming or docking such as Munc13 and vesicle fusion such as neuronal SNAREs. These components form complexes providing the molecular substructures of the presynaptic electron density. The same accounts for the postsynaptic compartment, which in case of excitatory synapses is dominated by a prominent postsynaptic density (PSD). The PSD harbors the protein PSD-95 and other scaffolding, as well as auxiliary proteins to cluster, stabilize, and regulate postsynaptic neurotransmitter receptors. Pre- and postsynapse are separated by the synaptic cleft, a compartment on its own with its morphological features influencing the spread and uptake of the exocytosed neurotransmitter, and this way strikingly modifies synapse function. Synapses of sensory systems appear to be molecularly and morphologically distinct in order to reliably mediate tonic signaling. Thus, synapse structure determines its functionality and identity. This Special Issue describes, which molecules determine—and how—synapse structure and function.

Prof. Dr. Carolin Wichmann
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • structure–function
  • synapse
  • protein composition
  • presynapse
  • postsynapse
  • synaptic cleft
  • ultrastucture

Published Papers (5 papers)

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Research

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22 pages, 10155 KiB  
Article
Heterogeneous Presynaptic Distribution of Munc13 Isoforms at Retinal Synapses and Identification of an Unconventional Bipolar Cell Type with Dual Expression of Munc13 Isoforms: A Study Using Munc13-EXFP Knock-in Mice
by Kaspar Gierke, Julia von Wittgenstein, Maike Hemmerlein, Jenny Atorf, Anneka Joachimsthaler, Jan Kremers, Benjamin H. Cooper, Frederique Varoqueaux, Hanna Regus-Leidig and Johann Helmut Brandstätter
Int. J. Mol. Sci. 2020, 21(21), 7848; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21217848 - 22 Oct 2020
Cited by 3 | Viewed by 2606
Abstract
Munc13 isoforms are constituents of the presynaptic compartment of chemical synapses, where they govern important steps in preparing synaptic vesicles for exocytosis. The role of Munc13-1, -2 and -3 is well documented in brain neurons, but less is known about their function and [...] Read more.
Munc13 isoforms are constituents of the presynaptic compartment of chemical synapses, where they govern important steps in preparing synaptic vesicles for exocytosis. The role of Munc13-1, -2 and -3 is well documented in brain neurons, but less is known about their function and distribution among the neurons of the retina and their conventional and ribbon-type chemical synapses. Here, we examined the retinae of Munc13-1-, -2-, and -3-EXFP knock-in (KI) mice with a combination of immunocytochemistry, physiology, and electron microscopy. We show that knock-in of Munc13-EXFP fusion proteins did not affect overall retinal anatomy or synapse structure, but slightly affected synaptic transmission. By labeling Munc13-EXFP KI retinae with specific antibodies against Munc13-1, -2 and -3, we found that unlike in the brain, most retinal synapses seem to operate with a single Munc13 isoform. A surprising exception to this rule was type 6 ON bipolar cells, which expressed two Munc13 isoforms in their synaptic terminals, ubMunc13-2 and Munc13-3. The results of this study provide an important basis for future studies on the contribution of Munc13 isoforms in visual signal processing in the mammalian retina. Full article
(This article belongs to the Special Issue Molecular Structure and Function of Synapses)
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19 pages, 5614 KiB  
Article
Deep Learning-Assisted High-Throughput Analysis of Freeze-Fracture Replica Images Applied to Glutamate Receptors and Calcium Channels at Hippocampal Synapses
by David Kleindienst, Jacqueline Montanaro, Pradeep Bhandari, Matthew J. Case, Yugo Fukazawa and Ryuichi Shigemoto
Int. J. Mol. Sci. 2020, 21(18), 6737; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186737 - 14 Sep 2020
Cited by 9 | Viewed by 2839
Abstract
The molecular anatomy of synapses defines their characteristics in transmission and plasticity. Precise measurements of the number and distribution of synaptic proteins are important for our understanding of synapse heterogeneity within and between brain regions. Freeze–fracture replica immunogold electron microscopy enables us to [...] Read more.
The molecular anatomy of synapses defines their characteristics in transmission and plasticity. Precise measurements of the number and distribution of synaptic proteins are important for our understanding of synapse heterogeneity within and between brain regions. Freeze–fracture replica immunogold electron microscopy enables us to analyze them quantitatively on a two-dimensional membrane surface. Here, we introduce Darea software, which utilizes deep learning for analysis of replica images and demonstrate its usefulness for quick measurements of the pre- and postsynaptic areas, density and distribution of gold particles at synapses in a reproducible manner. We used Darea for comparing glutamate receptor and calcium channel distributions between hippocampal CA3-CA1 spine synapses on apical and basal dendrites, which differ in signaling pathways involved in synaptic plasticity. We found that apical synapses express a higher density of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and a stronger increase of AMPA receptors with synaptic size, while basal synapses show a larger increase in N-methyl-D-aspartate (NMDA) receptors with size. Interestingly, AMPA and NMDA receptors are segregated within postsynaptic sites and negatively correlated in density among both apical and basal synapses. In the presynaptic sites, Cav2.1 voltage-gated calcium channels show similar densities in apical and basal synapses with distributions consistent with an exclusion zone model of calcium channel-release site topography. Full article
(This article belongs to the Special Issue Molecular Structure and Function of Synapses)
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27 pages, 10571 KiB  
Article
Synaptic Organization of the Human Temporal Lobe Neocortex as Revealed by High-Resolution Transmission, Focused Ion Beam Scanning, and Electron Microscopic Tomography
by Astrid Rollenhagen, Bernd Walkenfort, Rachida Yakoubi, Sarah A. Klauke, Sandra F. Schmuhl-Giesen, Jacqueline Heinen-Weiler, Sylvia Voortmann, Brigitte Marshallsay, Tayfun Palaz, Ulrike Holz, Mike Hasenberg and Joachim H.R. Lübke
Int. J. Mol. Sci. 2020, 21(15), 5558; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21155558 - 03 Aug 2020
Cited by 9 | Viewed by 3076
Abstract
Modern electron microscopy (EM) such as fine-scale transmission EM, focused ion beam scanning EM, and EM tomography have enormously improved our knowledge about the synaptic organization of the normal, developmental, and pathologically altered brain. In contrast to various animal species, comparably little is [...] Read more.
Modern electron microscopy (EM) such as fine-scale transmission EM, focused ion beam scanning EM, and EM tomography have enormously improved our knowledge about the synaptic organization of the normal, developmental, and pathologically altered brain. In contrast to various animal species, comparably little is known about these structures in the human brain. Non-epileptic neocortical access tissue from epilepsy surgery was used to generate quantitative 3D models of synapses. Beside the overall geometry, the number, size, and shape of active zones and of the three functionally defined pools of synaptic vesicles representing morphological correlates for synaptic transmission and plasticity were quantified. EM tomography further allowed new insights in the morphological organization and size of the functionally defined readily releasable pool. Beside similarities, human synaptic boutons, although comparably small (approximately 5 µm), differed substantially in several structural parameters, such as the shape and size of active zones, which were on average 2 to 3-fold larger than in experimental animals. The total pool of synaptic vesicles exceeded that in experimental animals by approximately 2 to 3-fold, in particular the readily releasable and recycling pool by approximately 2 to 5-fold, although these pools seemed to be layer-specifically organized. Taken together, synaptic boutons in the human temporal lobe neocortex represent unique entities perfectly adapted to the “job” they have to fulfill in the circuitry in which they are embedded. Furthermore, the quantitative 3D models of synaptic boutons are useful to explain and even predict the functional properties of synaptic connections in the human neocortex. Full article
(This article belongs to the Special Issue Molecular Structure and Function of Synapses)
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Review

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31 pages, 3952 KiB  
Review
Molecular Assembly and Structural Plasticity of Sensory Ribbon Synapses—A Presynaptic Perspective
by Roos Anouk Voorn and Christian Vogl
Int. J. Mol. Sci. 2020, 21(22), 8758; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228758 - 19 Nov 2020
Cited by 11 | Viewed by 4961
Abstract
In the mammalian cochlea, specialized ribbon-type synapses between sensory inner hair cells (IHCs) and postsynaptic spiral ganglion neurons ensure the temporal precision and indefatigability of synaptic sound encoding. These high-through-put synapses are presynaptically characterized by an electron-dense projection—the synaptic ribbon—which provides structural scaffolding [...] Read more.
In the mammalian cochlea, specialized ribbon-type synapses between sensory inner hair cells (IHCs) and postsynaptic spiral ganglion neurons ensure the temporal precision and indefatigability of synaptic sound encoding. These high-through-put synapses are presynaptically characterized by an electron-dense projection—the synaptic ribbon—which provides structural scaffolding and tethers a large pool of synaptic vesicles. While advances have been made in recent years in deciphering the molecular anatomy and function of these specialized active zones, the developmental assembly of this presynaptic interaction hub remains largely elusive. In this review, we discuss the dynamic nature of IHC (pre-) synaptogenesis and highlight molecular key players as well as the transport pathways underlying this process. Since developmental assembly appears to be a highly dynamic process, we further ask if this structural plasticity might be maintained into adulthood, how this may influence the functional properties of a given IHC synapse and how such plasticity could be regulated on the molecular level. To do so, we take a closer look at other ribbon-bearing systems, such as retinal photoreceptors and pinealocytes and aim to infer conserved mechanisms that may mediate these phenomena. Full article
(This article belongs to the Special Issue Molecular Structure and Function of Synapses)
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21 pages, 2845 KiB  
Review
Quantitative Synaptic Biology: A Perspective on Techniques, Numbers and Expectations
by Sofiia Reshetniak, Rubén Fernández-Busnadiego, Marcus Müller, Silvio O. Rizzoli and Christian Tetzlaff
Int. J. Mol. Sci. 2020, 21(19), 7298; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197298 - 02 Oct 2020
Cited by 3 | Viewed by 2978
Abstract
Synapses play a central role for the processing of information in the brain and have been analyzed in countless biochemical, electrophysiological, imaging, and computational studies. The functionality and plasticity of synapses are nevertheless still difficult to predict, and conflicting hypotheses have been proposed [...] Read more.
Synapses play a central role for the processing of information in the brain and have been analyzed in countless biochemical, electrophysiological, imaging, and computational studies. The functionality and plasticity of synapses are nevertheless still difficult to predict, and conflicting hypotheses have been proposed for many synaptic processes. In this review, we argue that the cause of these problems is a lack of understanding of the spatiotemporal dynamics of key synaptic components. Fortunately, a number of emerging imaging approaches, going beyond super-resolution, should be able to provide required protein positions in space at different points in time. Mathematical models can then integrate the resulting information to allow the prediction of the spatiotemporal dynamics. We argue that these models, to deal with the complexity of synaptic processes, need to be designed in a sufficiently abstract way. Taken together, we suggest that a well-designed combination of imaging and modelling approaches will result in a far more complete understanding of synaptic function than currently possible. Full article
(This article belongs to the Special Issue Molecular Structure and Function of Synapses)
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