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Cited by 603Neuroscience and Neuropharmacology ResearchGenetics and Neurodevelopmental DisordersNicotinic Acetylcholine Receptors Study

The Postsynaptic Organization of Synapses

Open access
Sheng, M., Kim, E.·2011·Cold Spring Harbor Perspectives in Biology
DOI 10.1101/cshperspect.a005678PMC PMC3225953
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Abstract

The postsynaptic side of the synapse is specialized to receive the neurotransmitter signal released from the presynaptic terminal and transduce it into electrical and biochemical changes in the postsynaptic cell. The cardinal functional components of the postsynaptic specialization of excitatory and inhibitory synapses are the ionotropic receptors (ligand-gated channels) for glutamate and γ-aminobutyric acid (GABA), respectively. These receptor channels are concentrated at the postsynaptic membrane and embedded in a dense and rich protein network comprised of anchoring and scaffolding molecules, signaling enzymes, cytoskeletal components, as well as other membrane proteins. Excitatory and inhibitory postsynaptic specializations are quite different in molecular organization. The postsynaptic density of excitatory synapses is especially complex and dynamic in composition and regulation; it contains hundreds of different proteins, many of which are required for cognitive function and implicated in psychiatric illness.

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Crossref · 10.1101/cshperspect.a005678

Cites

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Claims the paper makes

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  • Premisecitation

    The PSD was first seen in electron micrographs as an electron-dense thickening of the postsynaptic membrane apposed to the presynaptic active zone.

    “The PSD was first observed in electron micrographs as a fuzzy electron-dense thickening of the postsynaptic membrane that is apposed to the presynaptic active zone (hence the term”
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    • cites Gray 1959

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    • cites Siekevitz 1985

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  • Premisecitation

    PSD-95 appears to stabilize NMDA receptors at the cell surface.

    “In this way, PSD-95 appears to stabilize NMDA receptors at the cell surface (Roche et al. 2001;Prybylowski et al. 2005).”
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  • Premisecitation

    During initial axon-dendrite contact, interactions of pre- and postsynaptic cell adhesion molecules may determine the specificity of axodendritic contacts and drive synapse formation and maturation.

    “During the initial contact of axons and dendrites, the interaction of pre-and postsynaptic cell adhesion molecules may determine the specific-ity of axodendritic contacts and drive synapse formation and maturation (Craig and Kang 2007;Sudhof 2008;Shen and Scheiffele 2010).”
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    • cites Sudhof 2008

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  • Interpretationreasoning
    § The Postsynaptic Organization of Synapses

    Mechanisms of excitatory postsynaptic signaling differ between neuronal cell types.

    “This suggests that mechanisms of excitatory postsynaptic signaling differ between neuronal cell types.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: CaMKIIa is selectively present at PSDs of glutamatergic neurons, whereas ErbB4 and citron are mainly present at postsynaptic sites on GABAergic interneurons in the hippocampus.
  • Premisecitation

    Peptide sequencing in the 1990s identified abundant PSD proteins including PSD-95 and CaMKII.

    “In the 1990s, peptide sequencing of PSD components separated by gel electrophoresis enabled the identification of a variety of abun-dant PSD proteins, including PSD-95 and calcium calmodulin-dependent kinase II (CaM-KII) (Cho et al. 1992;Walsh and Kuruc 1992;Kennedy 2000).”
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    • cites Walsh and Kuruc 1992

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    • cites Kennedy 2000

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    Premisecitation

    N-cadherin is dynamically involved in transsynaptic signaling and structural and functional synaptic plasticity.

    “N-cadherin is dynamically involved in transsynaptic signaling and structural/functional synaptic plasticity (Tai et al. 2008).”
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    Premisecitation
    § The Postsynaptic Organization of Synapses

    PSD protein composition varies considerably between brain regions and probably between cell types.

    “It should be noted that PSD protein composition varies considerably between different brain regions and probably between different cell types (Zhang et al. 1999;Cheng et al. 2006;Vullhorst et al. 2009).”
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    Premisecitation

    Peng et al. identified 400 PSD proteins in 13 functional groups, with actin-cytoskeletal, kinase signaling, and GTPase signaling pathways highly represented.

    “For instance, Peng et al. identified 400 PSD proteins and categorized them into 13 functional groups, of which actin-cytoskeletal, kinase signaling and GTPase signaling pathways were highly represented (Fig. 1A) (Peng et al. 2004).”
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    Premisecitation

    The average PSD has a calculated molecular mass of 1 gigadalton, corresponding to about 10,000 copies of a 100 kDa protein.

    “The molecular mass of the average PSD has been calculated to be 1 gigadalton (Chen et al. 2005), which would correspond to 10,000 copies of a 100 kDa protein.”
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    Premisecitation

    Neuroligin cytoplasmic tails bind PSD scaffold proteins including PSD-95, and presynaptic neurexins bind CASK, providing a transsynaptic link between the PSD and the presynaptic active zone.

    “The cytoplasmic tails of neuroligins bind to PSD scaffold proteins including PSD-95 (Irie et al. 1997), whereas presynaptic neurexins bind to scaffolds such as CASK (Hata et al. 1996); such sets of protein -protein interactions provide a transsynaptic link between the PSD and the presynaptic active zone.”
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    • cites Hata et al. 1996

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    Premisecitation
    § The Postsynaptic Organization of Synapses

    Activation of NMDA receptors leads to phosphorylation of more than 100 PSD proteins, and different postsynaptic receptors induce differential phosphorylation in overlapping PSD proteins.

    “For instance, activation of NMDA receptors led to the phosphorylation of .100PSD proteins, and activation of different postsynaptic receptors (i.e., NMDA vs. metabotropic glutamate receptors) induces differential phosphorylation in overlapping PSD proteins (Coba et al. 2009).”
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    Premisecitation

    N-cadherin is present in the PSD at about 30 copies per average PSD and is critical for synapse integrity.

    “The classic adhesion molecule N-cadherin is also present in the PSD ( 30 copies in an average size PSD) and critical for synapse integrity (Tai et al. 2008).”
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    Premisecitation

    The PSD is a proteinaceous organelle attached to the postsynaptic plasma membrane and held by cytoplasmic actin filaments.

    “The PSD is essentially a proteinaceous organelle attached to the postsynaptic plasma membrane and held by cytoplasmic actin filaments (Siekevitz 1985;Kennedy 2000;Sheng and Kim 2002;Funke et al. 2004).”
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    • cites Siekevitz 1985

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    • cites Kennedy 2000

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    • cites Sheng and Kim 2002

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    Premisecitation

    Phosphorylation of GluN2 subunits affects their interaction with PSD-95 and regulates GluN2 subunit composition at synapses.

    “Phosphorylation of GluN2 subunits affects their interaction with PSD-95 and regulates GluN2 subunit composition at synapses (Chen and Roche 2007;Sanz-Clemente et al. 2010).”
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    • cites Chen and Roche 2007

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    • cites Sanz-Clemente et al. 2010

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    Premisecitation

    CaMKIIa and CaMKIIb are the most abundant PSD proteins, with 4800 and 800 copies in an average PSD, respectively.

    “CaMKIIa and CaMKIIb are by far the most abundant proteins, with 4800 and 800 copies in an average size PSD, respectively.”
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    • cites Sugiyama et al. 2005

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    Premisecitation

    PSD-95 family scaffolds (about 400 copies, of which 300 are PSD-95) and SynGAP (360 copies) are highly abundant in the PSD.

    “Other highly abundant molecules are scaffolds of the PSD-95 family ( 400 copies, of which 300 are PSD-95) and SynGAP (a Ras GTPase-activating protein [GAP] that binds to PSD-95; 360 copies).”
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    Premisecitation

    PSD-95 binds multiple other PSD proteins including SynGAP and GKAP, and GKAP interacts with Shank.

    “Similarly, PSD-95 was found to bind to multiple other PSD proteins, including SynGAP and GKAP; the latter in turn interacts with Shank (Funke et al. 2004;Kim and Sheng 2004).”
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    • cites Kim and Sheng 2004

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    Premisecitation

    PSDs are heterogeneous in size, with diameters of 200-800 nm (mean 300-400 nm) and thicknesses of 30-60 nm.

    “They are highly heterogeneous in size: diameter 200-800 nm (mean 300-400 nm) and thickness 30-60 nm (Carlin et al. 1980).”
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    • cites Carlin et al. 1980

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    Premisecitation

    N-cadherin binds presynaptic N-cadherin, AMPA receptors, and b-catenin, which links it to actin filaments.

    “In addition to binding in homophilic fashion to presynaptic N-cadherin, N-cadherin can also bind to AMPA receptors (Saglietti et al. 2007) and to b-catenin, a protein of the PSD that links N-cadherin to actin filaments.”
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    Interpretationreasoning

    Mass spectrometry surveys may have missed true PSD proteins that are rare or loosely associated with the PSD.

    “Conversely, MS surveys may have missed true PSD proteins that are rare in abundance or loosely associated with the PSD.”
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    Premisecitation

    PSD-95 family proteins are much more numerous than NMDA and AMPA receptor complexes, which number about 15-20 each in the PSD.

    “The number of PSD-95 family proteins is much greater than the number of NMDA and a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor complexes measured in the PSD ( 15-20 of each).”
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    Premisecitation

    PSD size correlates with dendritic spine size and with the abundance of postsynaptic glutamate receptors.

    “The size of the PSD correlates with the size of the dendritic spine in which they are located and with the abundance of postsynaptic glutamate receptors (Kasai et al. 2003), consistent with the idea that bigger synapses are stronger synapses.”
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    Premisecitation

    PSD-95 contains three PDZ domains, allowing it to interact with many other PSD proteins.

    “Three PDZ domains are found in PSD-95 (a founding member of the PDZ protein family), allowing it to interact with many other proteins of the PSD (Kim and Sheng 2004).”
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    • cites Kim and Sheng 2004

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    Premisecitation

    Overexpression of PSD-95 in hippocampal slices increases AMPA receptor-mediated synaptic transmission that occludes LTP.

    “For instance, overexpression of PSD-95 in hippocampal slices increases AMPA receptormediated synaptic transmission that occludes LTP (Stein et al. 2003;Ehrlich and Malinow 2004;Beique et al. 2006).”
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    • cites Ehrlich and Malinow 2004

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    Premisecitation

    CaMKIIb binds F-actin and stabilizes dendritic spine structure.

    “CaMKIIb also performs a structural role by binding to F-actin and stabilizing dendritic spine structure (Okamoto et al. 2007).”
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    Premisecitation

    Shank family proteins are large (about 200 kDa) and contain multiple protein interaction domains and undergo differential splicing.

    “The Shank family of scaffolds (Shank1 -3) (Sheng and Kim 2000;Boeckers et al. 2002) are large proteins ( 200 kDa) with multiple protein interaction domains that undergo differential splicing (Fig. 2).”
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    • cites Sheng and Kim 2000

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    • cites Boeckers et al. 2002

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    Premisecitation

    CaMKIIa is typically activated by calcium influx through NMDA receptors, stimulates synaptic delivery of AMPA receptors, and is critical for LTP.

    “CaMKIIa-which is typically activated by calcium influx through NMDA receptors-stimulates synaptic delivery of AMPA receptors and is critical for LTP (Hayashi et al. 2000).”
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    Premisecitation

    Ras and Rap regulate AMPA receptor trafficking during LTP and LTD, respectively.

    “for instance, Ras and Rap regulate AMPA receptor trafficking during LTP and LTD, respectively (Zhu et al. 2002)”
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    Premisecitation

    IRSp53 interacts with PSD-95 and Shank and acts downstream of Rac1 to regulate actin polymerization in dendritic spines.

    “Other scaffolds of the PSD include IRSp53 (insulin substrate protein of 53 kDa), which directly interacts with PSD-95 and Shank, and acts as a downstream effector of Rac1 for the regulation of actin polymerization in dendritic spines (Soltau et al. 2004;Choi et al. 2005).”
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    Interpretationcitation

    It is unlikely that an increase in postsynaptic PSD-95 accounts for the early phase of LTP, because PSD-95 does not accumulate in synapses during E-LTP.

    “However, it seems unlikely that an increase in postsynaptic PSD-95 accounts for the early phase of LTP (E-LTP), because PSD-95 does not accumulate in synapses during E-LTP (Steiner et al. 2008).”
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    Premisecitation

    RNAi knockdown of PSD-95 causes PSD disintegration, demonstrating PSD-95's crucial role in PSD organization.

    “The crucial role of PSD-95 in organization of the PSD is shown by the PSD disintegration that occurs on RNAi knockdown of PSD-95 (Chen et al. 2011).”
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    Premisecitation

    CaMKIIa binds a variety of PSD proteins including NMDA receptors; this interaction promotes synaptic localization of CaMKIIa and locks CaMKII in an active conformation.

    “CaMKIIa binds a variety of PSD proteins including NMDA receptors; the latter interaction not only promotes synaptic localization of CaMKIIa but also”
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    Premisecitation

    Overexpression of PSD-95 increases AMPA receptor-mediated excitatory synaptic transmission, whereas RNAi knockdown decreases it, with relatively little effect on NMDA receptor-mediated transmission.

    “Overexpression of PSD-95 increases AMPA receptor-mediated excitatory synaptic transmission (El-Husseini et al. 2000), whereas RNAi knockdown of PSD-95 decreases it (Elias et al. 2006;Futai et al. 2007), with relatively little effect on NMDA receptor-mediated transmission.”
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    Premisecitation

    AMPA receptor binding scaffolds GRIP and PICK1 are present but not selectively enriched in the PSD, suggesting roles primarily in AMPA receptor trafficking.

    “AMPA receptor binding scaffolds GRIP and PICK1 are present but not selectively enriched in the PSD, suggesting they have roles primarily in AMPA receptor trafficking (Shepherd and Huganir 2007).”
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    Premisecitation

    In mature neurons, the PSD undergoes continuous molecular turnover under basal conditions and changes more with activity.

    “Even in mature neurons, the PSD undergoes continual molecular turnover under basal conditions and shows larger changes in response to activity (Inoue and Okabe 2003).”
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    Premisecitation

    LTD is impaired by RNAi knockdown or genetic disruption of PSD-95 in mice and can be enhanced by PSD-95 overexpression.

    “LTD is impaired by RNAi knockdown or genetic disruption of PSD-95 in mice, and it can be enhanced by PSD-95 overexpression (Migaud et al. 1998;Beique and Andrade 2003;Stein et al. 2003;Ehrlich et al. 2007;Carlisle et al. 2008;Xu et al. 2008).”
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    Premisecitation

    By binding to TARPs, PSD-95 recruits AMPA receptors to synapses and can thereby determine synaptic strength.

    “By binding to the carboxyl terminus of transmembrane TARPs (accessory subunits of AMPA receptors), PSD-95 recruits AMPA receptors to synapses and can thereby determine synaptic strength (Chen et al. 2000;Schnell et al. 2002;Nicoll et al. 2006;Bats et al. 2007).”
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    Premisecitation

    Gephyrin is critical for glycine receptor clustering at inhibitory synapses but appears less important for GABA A receptor clustering.

    “Gephyrin is critical for glycine receptor clustering at inhibitory synapses, but appears less important for GABA A receptor clustering (Kneussel et al. 2001;Levi et al. 2004).”
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    Premisecitation

    PSD-95 is dynamically exchanged between neighboring PSDs in cortical neurons in vivo, with median retention times in individual spines of 20-100 min depending on age.

    “PSD-95 is dynamically exchanged between neighboring PSDs in cortical neurons in vivo, with median synaptic retention times of PSD-95 within individual spines of 20 -100 min depending on age (Gray et al. 2006).”
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    Premisecitation

    Inhibitory synapses are mainly formed on dendritic shafts or around the neuronal cell body and show only a slight electron-dense thickening by EM, described as symmetric (type II) synapses.

    “Inhibitory synapses are mainly formed on the shaft of dendrites or around the neuronal cell body, and by EM, they show only a slight electron-dense thickening associated with the postsynaptic membrane and hence were described as symmetric (type II) synapses (Gray 1959).”
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    Premisecitation

    About a dozen binding partners of gephyrin have been identified.

    “About a dozen binding partners of gephyrin have been identified (Fritschy et al. 2008).”
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    Premisecitation

    GSK3b phosphorylation of gephyrin at Ser-270 impairs gephyrin clustering and inhibitory transmission.

    “GSK3b phosphorylation of Ser-270 impairs gephyrin clustering and inhibitory transmission (Tyagarajan et al. 2011).”
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    Premisecitation

    Gephyrin-associated dynein light chains have been implicated in motor-dependent transport of the gephyrin-receptor complex along microtubules/actin filaments and translocation of gephyrin from the cytoplasm to a submembraneous compartment.

    “In addition, gephyrin-associated dynein light chains have been implicated in motor-dependent transport of the gephyrin-receptor complex along microtubules/actin filaments and translocation of gephyrin from the cytoplasmic to a submembraneous compartment (Fig. 5) (Fuhrmann et al. 2002).”
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    Premisecitation

    Neurexin interacts with GABA A receptors and suppresses GABAergic transmission, independent of neuroligins.

    “Lastly, independent of neuroligins, neurexin has been found to interact with GABA A receptors and suppress GABAergic transmission (Zhang et al. 2010).”
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    Premisecitation

    Impaired inhibitory transmission induced by triple knockdown of neuroligins 1-3 is rescued by neuroligin 3 expression, though less than by neuroligin 2.

    “The impaired inhibitory transmission induced by triple knockdown of neuroligins 1 -3 is rescued by neuroligin 3 expression, although to a lesser extent than with neuroligin 2, suggesting that neuroligin 3 contributes to inhibitory transmission (Shipman et al. 2011).”
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    Neuroligin 2 interacts extracellularly with presynaptic neurexins on GABAergic axons and intracellularly recruits postsynaptic gephyrin and gephyrin-bound collybistin.

    “Neuroligin 2 interacts on the extracellular side with presynaptic neurexins on GABAergic axons; via intracellular interactions it recruits postsynaptic gephyrin and gephyrinbound collybistin, a GEF for Cdc42 (Graf et al. 2004;Varoqueaux et al. 2004;Chih et al. 2005;Craig and Kang 2007;Poulopoulos et al. 2009).”
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  • The paper relies on this without support.

    Excitatory and inhibitory postsynaptic specializations differ substantially in molecular organization.

    “Excitatory and inhibitory postsynaptic specializations are quite different in molecular organization.”

  • The paper relies on this without support.

    Much more is known about the postsynaptic organization of central excitatory synapses than about inhibitory synapses.

    “In part because of their greater abundance and distinctive structure, much more is known about the postsynaptic organization of central excitatory (glutamatergic) synapses.”

  • The paper relies on this without support.

    The generally accepted roles of the PSD are to mediate pre- and postsynaptic membrane apposition, cluster postsynaptic receptors, and couple receptor activation to biochemical signaling.

    “The generally accepted roles for the PSD are to mediate the apposition of pre-and postsynaptic membranes, to cluster postsynaptic receptors, and to couple the activation of postsynaptic receptors to biochemical signaling events in the postsynaptic neuron.”

  • The paper relies on this without support.

    Inhibitory synapses are formed on dendritic shafts, cell bodies, and axon initial segments.

    “In contrast, inhibitory synapses are formed on the shaft of dendrites, or on cell bodies and axon initial segments.”

  • The paper relies on this without support.

    CaMKIIa is selectively present at PSDs of glutamatergic neurons, whereas ErbB4 and citron are mainly present at postsynaptic sites on GABAergic interneurons in the hippocampus.

    “For instance, CaMKIIa is selectively present at the PSDs of glutamatergic neurons, whereas ErbB4 and citron are mainly present at postsynaptic sites on GABAergic interneurons in the hippocampus.”

  • The paper relies on this without support.

    Postsynaptic cell adhesion molecules bind specific presynaptic membrane proteins to mediate synaptic contact and alignment.

    “Postsynaptic cell adhesion molecules within and surrounding the PSD bind to specific proteins in the presynaptic membrane to mediate the synaptic contact and alignment.”

  • The paper relies on this without support.

    Stronger synapses are correlated with larger PSDs and higher content of PSD-95 and AMPA receptors.

    “Consistent with the control of synaptic strength by PSD-95, stronger synapses are correlated with larger PSDs and a higher content of PSD-95 and AMPA receptors.”

  • The paper relies on this without support.

    The carboxyl terminus of GKAP interacts with the PDZ domain of Shank, which binds Homer.

    “The carboxyl terminus of GKAP, in turn, interacts with the PDZ domain of Shank, which binds to Homer.”

  • The paper relies on this without support.

    GFP-tagged PSD-95 localizes specifically in the PSD.

    “The dynamic behavior of PSDs in living neurons in culture and in vivo has been typically visualized by GFP-tagged PSD-95, which localizes specifically in the PSD.”

  • The paper relies on this without support.

    GABA A receptors and glycine receptors are the cardinal neurotransmitter receptors of central inhibitory synapses.

    “The cardinal neurotransmitter receptors of central inhibitory synapses are the GABA A receptors and glycine receptors.”

  • The paper relies on this without support.

    Gephyrin can self-multimerize and form a hexagonal lattice.

    “Reminiscent of the major scaffolds in excitatory PSDs, gephyrin can self-multimerize and form a hexagonal lattice, and thus may function as a postsynaptic scaffold through which GABA A /glycine receptors functionally interact with gephyrin-associated proteins.”
11 of 11

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  • Shank proteins act as scaffolds in the postsynaptic density of excitatory synapses and control the organization of postsynaptic signalling complexes and synapse morphology and function.

    “Shank proteins function as scaffolds in the PSD of excitatory synapses that regulate the organization of postsynaptic signalling complexes, as well as the morphology and function of synapses17–19.”

    From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [19]

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Authors
Sheng, M., & Kim, E.
Affiliations
  • Genentech (US)
  • Korea Advanced Institute of Science and Technology (KR)
Corresponding author
Kim, E.
ORCID
Venue
Cold Spring Harbor Perspectives in Biology
Publisher
Cold Spring Harbor Laboratory
Published
2011-11-01
Volume
3
Issue
12
Pages
a005678-a005678
ISSN
1943-0264 (ISSN-L)
DOI
10.1101/cshperspect.a005678
PMC
PMC3225953
OpenAlex
W2154626303
Semantic Scholar
0ec07cc6e2004ec14e15af638f1b572d6579aef7
Cited by
603
References
209
Citations by year
2026: 39 · 2025: 43 · 2024: 48 · 2023: 42 · 2022: 46 · 2021: 71 · 2020: 48 · 2019: 54 · 2018: 47 · 2017: 39 · 2016: 38 · 2015: 32 · 2014: 26 · 2013: 21 · 2012: 8
Type
posted content
Language
en
Open access
Locations
  • Cold Spring Harbor Perspectives in Biology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
Keywords
postsynaptic specialization, synapses, postsynaptic density, glutamate receptors, GABA receptors, ligand-gated ion channels, excitatory synapses, inhibitory synapses, scaffold proteins, cytoskeleton, synaptic signaling, cognitive function, mental illness
MeSH terms
Disks Large Homolog 4 Protein, Animals, Membrane Proteins, Models, Biological, Synapses, Signal Transduction, Intracellular Signaling Peptides and Proteins, Mice, Guanylate Kinases, Post-Synaptic Density

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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