Abstract
The control of synaptic inhibition is crucial for normal brain function. More than 20 years ago, glycine and gamma-aminobutyric acid (GABA) were shown to be the two major inhibitory neurotransmitters. They can be released independently from different terminals or co-released from the same terminal to activate postsynaptic glycine and GABAA receptors. The anchoring protein gephyrin is involved in the postsynaptic accumulation of both glycine and GABAA receptors. In lower brain regions, both receptors can be concentrated in synapses, whereas in higher brain regions, glycine receptors are mostly excluded from postsynaptic sites. The activation of glycine and/or GABAA receptors determines the strength and precise timing of inhibition. Therefore, tight regulation of postsynaptic glycine versus GABAA receptor localization is crucial for optimizing synaptic inhibition in neurons. This review focuses on recent findings and discusses questions concerning the specificity of postsynaptic inhibitory neurotransmitter receptor accumulation during inhibitory synapse formation and development.
Similar content being viewed by others
References
Alsina B, Vu T, Cohen-Cory S (2001) Visualizing synapse formation in arborizing optic axons in vivo: dynamics and modulation by BDNF. Nat Neurosci 4:1093–1101
Bedford FK, Kittler JT, Jones SC, Sihra TS, Harvey RJ, Moss SJ (1999) GABA-A receptor subunits associate with specific gephyrin isoforms (Abstract no. 681.21). Soc Neurosci Abstracts 25:1712
Berridge MJ (1998) Neuronal calcium signaling. Neuron 21:13–26
Biederer T, Sara Y, Mozhayeva M, Atasoy D, Liu X, Kavalali ET, Südhof TC (2002) SynCAM, a synaptic adhesion molecule that drives synapse assembly. Science 297:1525–1531
Bootman MD, Lipp P, Berridge MJ (2001) The organisation and functions of local Ca(2+) signals. J Cell Sci 114:2213–2222
Borgdorff AJ, Choquet D (2002) Regulation of AMPA receptor lateral movements. Nature 417:649–653
Brickley SG, Cully-Candy SG, Farrant M (1996) Development of a tonic form of synaptic inhibition in rat cerebellar granule cells resulting from persistent activation of GABAA receptors. J Physiol (Lond) 497:753–759
Broughman JR, Shank LP, Takeguchi W, Schultz BD, Iwamoto T, Mitchell KE, Tomich JM (2002) Distinct structural elements that direct solution aggregation and membrane assembly in the channel-forming peptide M2GlyR. Biochemistry 41:7350–7358
Brunig I, Suter A, Knuesel I, Luscher B, Fritschy JM (2002) GABAergic terminals are required for postsynaptic clustering of dystrophin but not of GABA(A) receptors and gephyrin. J Neurosci 22:4805–4813
Cantallops I, Cline HT (2000) Synapse formation: if it looks like a duck and quacks like a duck..... Curr Biol 10:R620-R623
Christie SB, Miralles CP, De Blas AL (2002) GABAergic innervation organizes synaptic and extrasynaptic GABAA receptor clustering in cultured hippocampal neurons. J Neurosci 22:684–697
Colin I, Rostaing P, Triller A (1996) Gephyrin accumulates at specific plasmalemma loci during neuronal maturation in vitro. J Comp Neurol 374:467–479
Craig AM, Boudin H (2001) Molecular heterogeneity of central synapses: afferent and target regulation. Nat Neurosci 4:569–578
Dumoulin A, Levi S, Riveau B, Gasnier B, Triller A (2000) Formation of mixed glycine and GABAergic synapses in cultured spinal cord neurons. Eur J Neurosci 12:3883–3892
Essrich C, Lorez M, Benson JA, Fritschy JM, Luscher B (1998) Postsynaptic clustering of major GABAA receptor subtypes requires the gamma 2 subunit and gephyrin. Nat Neurosci 1:563–571
Gasnier B (2000) The loading of neurotransmitters into synaptic vesicles. Biochimie 82:327–337
Guastella J, Johnson CD, Stretton AO (1991) GABA-immunoreactive neurons in the nematode Ascaris. J Comp Neurol 307:584–597
Hardingham GE, Arnold FJ, Bading H (2001) A calcium microdomain near NMDA receptors: on switch for ERK-dependent synapse-to-nucleus communication. Nat Neurosci 4:565–566
Hoch W, Betz H, Becker CM (1989) Primary cultures of mouse spinal cord express the neonatal isoform of the inhibitory glycine receptor. Neuron 3:339–348
Hübner CA, Stein V, Hermans-Borgmeyer I, Meyer T, Ballanyi K, Jentsch TJ (2001) Disruption of KCC2 reveals an essential role of K-Cl cotransport already in early synaptic inhibition. Neuron 30:515–524
Jonas P, Bischofberger J, Sandkuhler J (1998) Corelease of two fast neurotransmitters at a central synapse. Science 281:419–424
Kaiser S, Blank M, Berg DK (2002) Maturation of postsynaptic nicotinic structures on autonomic neurons requires innervation but not cholinergic transmission. Eur J Neurosci 16:1–10
Kirsch J, Betz H (1998) Glycine-receptor activation is required for receptor clustering in spinal neurons. Nature 392:717–720
Kirsch J, Wolters I, Triller A, Betz H (1993) Gephyrin antisense oligonucleotides prevent glycine receptor clustering in spinal neurons. Nature 366:745–748
Klein R (2001) Excitatory Eph receptors and adhesive ephrin ligands. Curr Opin Cell Biol 13:196–203
Kneussel M, Brandstatter JH, Laube B, Stahl S, Muller U, Betz H (1999) Loss of postsynaptic GABA(A) receptor clustering in gephyrin-deficient mice. J Neurosci 19:9289–9297
Legendre P (2001) The glycinergic inhibitory synapse. Cell Mol Life Sci 58:760–793
Legendre P, Müller E, Badiu CI, Meier J, Vannier C, Triller A (2002) Desensitization of homomeric alpha1 glycine receptor increases with receptor density (abstract). Mol Pharmacol 62:(in press)
Levi S, Vannier C, Triller A (1998) Strychnine-sensitive stabilization of postsynaptic glycine receptor clusters. J Cell Sci 111:335–345
Levi S, Chesnoy-Marchais D, Sieghart W, Triller A (1999) Synaptic control of glycine and GABA(A) receptors and gephyrin expression in cultured motoneurons. J Neurosci 19:7434–7449
Levi S, Grady RM, Henry MD, Campbell KP, Sanes JR, Craig AM (2002) Dystroglycan is selectively associated with inhibitory GABAergic synapses but is dispensable for their differentiation. J Neurosci 22:4274–4285
Li J, Smolyar A, Sunder-Plassmann R, Reinherz EL (1996) Ligand-induced conformational change within the CD2 ectodomain accompanies receptor clustering: implication for molecular lattice formation. J Mol Biol 263:209–226
Lyons HR, Land MB, Gibbs TT, Farb DH (2001) Distinct signal transduction pathways for GABA-induced GABA(A) receptor down-regulation and uncoupling in neuronal culture: a role for voltage-gated calcium channels. J Neurochem 78:1114–1126
Mangin JM, Guyon A, Eugene D, Paupardin-Tritsch D, Legendre P (2002) Functional glycine receptor maturation in the absence of glycinergic input in dopaminergic neurones of the rat substantia nigra. J Physiol 542:685–697
Marty S, Wehrle R, Alvarez-Leefmans FJ, Gasnier B, Sotelo C (2002) Postnatal maturation of Na+, K+, 2Cl− cotransporter expression and inhibitory synaptogenesis in the rat hippocampus: an immunocytochemical analysis. Eur J Neurosci 15:233–245
Meier J, Meunier-Durmort C, Forest C, Triller A, Vannier C (2000a) Formation of glycine receptor clusters and their accumulation at synapses. J Cell Sci 113:2783–2795
Meier J, De Chaldee M, Triller A, Vannier C (2000b) Functional heterogeneity of gephyrins. Mol Cell Neurosci 16:566–577
Meier J, Vannier C, Serge A, Triller A, Choquet D (2001) Fast and reversible trapping of surface glycine receptors by gephyrin. Nat Neurosci 4:253–260
Meier J, Jüttner R, Kirischuk S, Grantyn R (2002) Synaptic anchoring of glycine receptors in developing collicular neurons under control of metabotropic glutamate receptor activity. Mol Cell Neurosci 21:324–340
Meier J, Akyeli J, Kirischuk S, Grantyn R (2003) GABAAR activity and PKC control inhibitory synaptogenesis in CNS tissue slices. Mol Cell Neurosci (in press)
Meyer G, Kirsch J, Betz H, Langosch D (1995) Identification of a gephyrin binding motif on the glycine receptor beta subunit. Neuron 15:563–572
Moss SJ, Smart TG (2001) Constructing inhibitory synapses. Nat Rev Neurosci 2:240–250
O'Brien JA, Berger AJ (1999) Cotransmission of GABA and glycine to brain stem motoneurons. J Neurophysiol 82:1638–1641
Poyatos I, Ponce J, Aragon C, Gimenez C, Zafra F (1997) The glycine transporter GLYT2 is a reliable marker for glycine-immunoreactive neurons. Brain Res Mol Brain Res 49:63–70
Radian R, Ottersen OP, Storm-Mathisen J, Castel M, Kanner BI (1990) Immunocytochemical localization of the GABA transporter in rat brain. J Neurosci 10:1319–1330
Rao A, Cha EM, Craig AM (2000a) Mismatched appositions of presynaptic and postsynaptic components in isolated hippocampal neurons. J Neurosci 20:8344–8353
Rao A, Harms KJ, Craig AM (2000b) Neuroligation: building synapses around the neurexin-neuroligin link. Nat Neurosci 3:747–749
Rivera C, Voipio J, Payne JA, Ruusuvuori E, Lahtinen H, Lamsa K, Pirvola U, Saarma M, Kaila K (1999) The K+/Cl− co-transporter KCC2 renders GABA hyperpolarizing during neuronal maturation. Nature 397:251–255
Rosenberg M, Meier J, Triller A, Vannier C (2001) Dynamics of glycine receptor insertion in the neuronal plasma membrane. J Neurosci 21:5036–5044
Roux MJ, Supplisson S (2000) Neuronal and glial glycine transporters have different stoichiometries. Neuron 25:373–383
Russier M, Kopysova IL, Ankri N, Ferrand N, Debanne D (2002) GABA and glycine co-release optimizes functional inhibition in rat brainstem motoneurons in vitro. J Physiol (Lond) 541:123–137
Sanes JR, Lichtman JW (2001) Induction, assembly, maturation and maintenance of a postsynaptic apparatus. Nat Rev Neurosci 2:791–805
Scheiffele P, Fan J, Choih J, Fetter R, Serafini T (2000) Neuroligin expressed in nonneuronal cells triggers presynaptic development in contacting axons. Cell 101:657–669
Scotti AL, Reuter H (2001) Synaptic and extrasynaptic gamma-aminobutyric acid type A receptor clusters in rat hippocampal cultures during development. Proc Natl Acad Sci USA 98:3489–3494
Seitanidou T, Triller A, Korn H (1988) Distribution of glycine receptors on the membrane of a central neuron: an immunoelectron microscopy study. J Neurosci 8:4319–4333
Shepherd GM, Erulker SD (1997) Century of the synapse: from Sherrington to the molecular biology of the synapse and beyond. Trends Neurosci 20:385–392
Studler B, Fritschy J, Brunig I (2002) GABAergic and glutamatergic terminals differentially influence the organization of GABAergic synapses in rat cerebellar granule cells in vitro. Neuroscience 114:123–133
Titmus MJ, Korn H, Faber DS (1996) Diffusion, not uptake, limits glycine concentration in the synaptic cleft. J Neurophysiol 75:1738–1752
Triller A, Cluzeaud F, Pfeiffer F, Betz H, Korn H (1985) Distribution of glycine receptors at central synapses: an immunoelectron microscopy study. J Cell Biol 101:683–688
Ulfhake B, Kellerth JO (1981) A quantitative light microscopic study of the dendrites of cat spinal alpha-motoneurons after intracellular staining with horseradish peroxidase. J Comp Neurol 202:571–583
Umeda T, Okabe S (2001) Visualizing synapse formation and remodeling: recent advances in real-time imaging of CNS synapses. Neurosci Res 40:291–300
Unwin N, Miyazawa A, Li J, Fujiyoshi Y (2002) Activation of the nicotinic acetylcholine receptor involves a switch in conformation of the alpha subunits. J Mol Biol 319:1165–1176
Acknowledgements
I am grateful to Dr. Rosemarie Grantyn for helpful suggestions with regard to this manuscript.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Meier, J. The enigma of transmitter-selective receptor accumulation at developing inhibitory synapses. Cell Tissue Res 311, 271–276 (2003). https://doi.org/10.1007/s00441-002-0694-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00441-002-0694-9