Glutamatergic Synapses: Molecular Organisation


One of the best understood and highly organised synapses is excitatory glutamatergic synapses. These synapses consist of post‐synaptic ionotropic glutamate receptors and pre‐synaptic glutamate localised inside pre‐synaptic vesicles. Glutamate binds to α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionic acid subtype glutamate receptors, giving rise to synaptic transmission. However, N‐methyl‐d‐aspartate subtype glutamate receptors function to induce the change in synaptic transmission, also known as the synaptic plasticity that underlies learning and memory. The subtypes and subunits of glutamate receptors exhibit distinct biophysical properties and play distinct physiological roles critical for synaptic function. The molecular organisation of the synapse includes intracellular scaffolding proteins, intercellular cell adhesion molecules to anchor synaptic architecture and a variety of signalling proteins (kinases, phosphatases, etc.). They function to support and/or mediate the cellular processes critical for synaptic transmission and plasticity, whereas their malfunction leads to diseases where synaptic plasticity is lost, such as Alzheimer disease and mental retardation.

Key Concepts:

  • Glutamatergic synapses are critical for our brain function.

  • Synaptic plasticity is critical for proper neuronal circuit formation.

  • Synaptic plasticity is the cellular model for learning, memory and other experience‐dependent brain functions.

  • History of neuronal activity plays a significant role in synaptic protein composition, which in turn governs synapse‐to‐nucleus signalling.

  • Scaffolding proteins, in addition to signalling proteins and receptors, are critical for synaptic plasticity.

  • Extrasynaptic NMDA receptor signalling plays distinct roles from synaptic NMDA receptor signalling.

Keywords: glutamate; synapse; AMPA receptors; synaptic plasticity; LTD; LTP; post‐synaptic density (PSD); scaffolding proteins; synaptic scaling; extrasynaptic NMDA receptors

Figure 1.

Synaptic transmission at basal state: glutamate ( ) released from synaptic terminal diffuses across synaptic cleft, binds to, and opens AMPA subtype glutamate receptors (AMPAR), leading to membrane depolarisation. NMDA subtype glutamate receptors (NMDAR) do not open because of magnesium ion ( ) blockade of channel pore. Extrasynaptic AMPAR and NMDAR do not have access to released glutamate because of clearance by glutamate transporters (Glu T) localised in glia or pre‐synaptic terminal.

Figure 2.

Schematics of scaffolding proteins, cell adhesion molecules (CAM) and signalling proteins in synapse organisations and plasticity. (a) PDZ domain containing scaffolding proteins: PSD95 and GRIP as two examples. (b) Signalling enzymes and their targeting proteins: CaMKII/PKA and PP1/PP2B along with their targeting proteins (NMDAR, AKAP79/150 and neurabin). (c) CAMs: NLG: neuroligin family CAMs, has four isoforms; LRRTM has at least four isoforms; N‐cadherin has many isoforms.



Aoto J, Nam CI, Poon MM, Ting P and Chen L (2008) Synaptic signaling by all‐trans retinoic acid in homeostatic synaptic plasticity. Neuron 60(2): 308–320.

Beattie EC, Carroll RC, Yu X et al. (2000) Regulation of AMPA receptor endocytosis by a signaling mechanism shared with LTD. Nature Neuroscience 3(12): 1291–1300.

Chen L, Chetkovich DM, Petralia RS et al. (2000) Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms. Nature 408(6815): 936–943.

Ehlers MD (2003) Activity level controls postsynaptic composition and signaling via the ubiquitin–proteasome system. Nature Neuroscience 6(3): 231–242.

Fu AKY, Hung K‐W, Fu W‐Y et al. (2011) APC(Cdh1) mediates EphA4‐dependent downregulation of AMPA receptors in homeostatic plasticity. Nature Neuroscience 14(2): 181–189.

Hardingham GE and Bading H (2010) Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nature Reviews. Neuroscience 11(10): 682–696.

Hardingham GE, Fukunaga Y and Bading H (2002) Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut‐off and cell death pathways. Nature Neuroscience 5(5): 405–414.

Hu JH, Park JM, Park S et al. (2010) Homeostatic scaling requires group I mGluR activation mediated by Homer1a. Neuron 68(6): 1128–1142.

Hu XD, Huang Q, Roadcap DW, Shenolikar SS and Xia H (2006) Actin‐associated neurabin‐protein phosphatase‐1 complex regulates hippocampal plasticity. Journal of Neurochemistry 98(6): 1841–1851.

Kato AS, Gill MB, Ho MT et al. (2011) Hippocampal AMPA receptor gating controlled by both TARP and cornichon proteins. Neuron 68(6): 1082–1096.

Li Z, Jo J, Jia JM et al. (2010) Caspase‐3 activation via mitochondria is required for long‐term depression and AMPA receptor internalization. Cell 141(5): 859–871.

Luscher C, Xia H, Beattie EC et al. (1999) Role of AMPA receptor cycling in synaptic transmission and plasticity. Neuron 24(3): 649–658.

Malenka RC and Bear MF (2004) LTP and LTD: an embarrassment of riches. Neuron 44(1): 5–21.

Malinow R and Malenka RC (2002) AMPA receptor trafficking and synaptic plasticity. Annual Review of Neuroscience 25: 103–126.

Nicoll RA, Tomita S and Bredt DS (2006) Auxiliary subunits assist AMPA‐type glutamate receptors. Science 311(5765): 1253–1256.

Pak DT and Sheng M (2003) Targeted protein degradation and synapse remodeling by an inducible protein kinase. Science 302(5649): 1368–1373.

Peineau S, Taghibiglou C, Bradley C et al. (2007) LTP inhibits LTD in the hippocampus via regulation of GSK3beta. Neuron 53(5): 703–717.

Seeburg DP, Feliu‐Mojer M, Gaiottino J, Pak DT and Sheng M (2008) Critical role of CDK5 and Polo‐like kinase 2 in homeostatic synaptic plasticity during elevated activity. Neuron 58(4): 571–583.

Sheng M and Hoogenraad CC (2007) The postsynaptic architecture of excitatory synapses: a more quantitative view. Annual Review of Biochemistry 76: 823–847.

Soden ME and Chen L (2011) Fragile X protein FMRP is required for homeostatic plasticity and regulation of synaptic strength by retinoic acid. Journal of Neuroscience 30(50): 16910–16921.

Stellwagen D and Malenka RC (2006) Synaptic scaling mediated by glial TNF‐alpha. Nature 440(7087): 1054–1059.

Tomita S, Stein V, Stocker TJ, Nicoll RA and Bredt DS (2005) Bidirectional synaptic plasticity regulated by phosphorylation of stargazin‐like TARPs. Neuron 45(2): 269–277.

Turrigiano GG, Leslie KR, Desai NS, Rutherford LC and Nelson SB (1998) Activity‐dependent scaling of quantal amplitude in neocortical neurons. Nature 391(6670): 892–896.

Tzingounis AV and Nicoll RA (2006) Arc/Arg3.1: linking gene expression to synaptic plasticity and memory. Neuron 52(3): 403–407.

Wang Z, Edwards JG, Riley N et al. (2008) Myosin Vb mobilizes recycling endosomes and AMPA receptors for postsynaptic plasticity. Cell 135(3): 535–548.

Xia P, Chen HS, Zhang D and Lipton SA (2010) Memantine preferentially blocks extrasynaptic over synaptic NMDA receptor currents in hippocampal autapses. Journal of Neuroscience 30(33): 11246–11250.

Zhu JJ, Qin Y, Zhao M, Van Aelst L and Malinow R (2002) Ras and Rap control AMPA receptor trafficking during synaptic plasticity. Cell 110(4): 443–455.

Further Reading

Chen L, Tracy T and Nam CI (2007) Dynamics of postsynaptic glutamate receptor targeting. Current Opinion in Neurobiology 17(1): 53–58.

Crego C, Landreth A and Silva AJ (2011) Molecular and Cellular Basis of Learning Difficulties in Genetic Disorders. In: eLS. Chichester: John Wiley & Sons Ltd. [doi:10.1002/9780470015902.a0022480].

Delaney KR and Stanley EE (2009) Calcium and Neurotransmitter Release. In: eLS. Chichester: John Wiley & Sons Ltd. [doi: 10.1002/9780470015902.a0000027.pub3].

Pang ZP and Sudhof TC (2010) Cell biology of Ca2+‐triggered exocytosis. Current Opinion in Cell Biology 22(4): 496–505.

Shepherd JD and Huganir RL (2007) The cell biology of synaptic plasticity: AMPA receptor trafficking. Annual Review of Cell and Developmental Biology 23: 613–643.

Sudhof TC (2008) Neuroligins and neurexins link synaptic function to cognitive disease. Nature 455(7215): 903–911.

Turrigiano GG (2008) The self‐tuning neuron: synaptic scaling of excitatory synapses. Cell 135(3): 422–435.

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Siddoway, Benjamin, Hou, Hailong, and Xia, Houhui(Dec 2011) Glutamatergic Synapses: Molecular Organisation. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0000235.pub2]