CoChat
Sign Up
Cited by 69Neuroscience and Neuropharmacology ResearchGenetics and Neurodevelopmental DisordersReceptor Mechanisms and Signaling

Tuning GABAergic Inhibition: Gephyrin Molecular Organization and Functions

Open access
Pizzarelli, Rocco, Griguoli, Marilena, Zacchi, Paola, Petrini, Enrica Maria, Barberis, Andrea, Cattaneo, Antonino, Cherubini, Enrico·2020·Neuroscience
DOI 10.1016/j.neuroscience.2019.07.036PMC PMC7351109
Open this paper in CoChat — free accountOpen PDF

Abstract

Rs to the cytoskeleton, thus ensuring the accurate accumulation of postsynaptic receptors at the right place. This protein undergoes several post-translational modifications which control protein-protein interaction and downstream signaling pathways. In addition, through the constant exchange of scaffolding elements and receptors in and out of synapses, gephyrin dynamically regulates synaptic strength and plasticity. The aim of the present review is to highlight recent findings on the functional role of gephyrin at GABAergic inhibitory synapses. We will discuss different approaches used to interfere with gephyrin in order to unveil its function. In addition, we will focus on the impact of gephyrin structure and distribution at the nanoscale level on the functional properties of inhibitory synapses as well as the implications of this scaffold protein in synaptic plasticity processes. Finally, we will emphasize how gephyrin genetic mutations or alterations in protein expression levels are implicated in several neuropathological disorders, including autism spectrum disorders, schizophrenia, temporal lobe epilepsy and Alzheimer's disease, all associated with severe deficits of GABAergic signaling. This article is part of a Special Issue entitled: Honoring Ricardo Miledi - outstanding neuroscientist of XX-XXI centuries.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.neuroscience.2019.07.036

Cites

5 of 5 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Gephyrin post-translational modifications modulate its affinity for GABAergic and glycinergic receptors, thus balancing inhibitory stability with plastic remodeling.

    “These modulate its affinity for GABAergic and glycinergic receptors, thus balancing inhibitory stability with plastic remodeling [57,58,59,60].”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [59]

    In the Introduction (‘Gephyrin at inhibitory synapses: features, regulations and roles’; page not provided), the review says gephyrin binds both GABAA and glycine receptors and that phosphorylation affects GABAA receptor dynamics and synaptic stabilization. It also links gephyrin to inhibitory plasticity. The cited passages do not establish that gephyrin’s post-translational modifications modulate its binding affinity for both receptor types; that specific mechanism is unsupported. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Genetic mutations or alterations in gephyrin expression are implicated in several disorders, specifically including temporal lobe epilepsy, autism, and Alzheimer's disease.

    “Genetic mutations or alterations in gephyrin expression are implicated in several disorders, specifically including temporal lobe epilepsy, as well as autism and Alzheimer’s disease [59].”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [59]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 112

  1. Agarwal S Tannenberg RK Dodd PR Reduced expression of the inhibitory synapse scaffolding protein gephyrin in Alzheimer's disease J Alzheimers Dis 14 2008 313 321 18599957
  2. Antonelli R Pizzarelli R Pedroni A Fritschy JM Del Sal G Cherubini E Zacchi P Pin1-dependent signalling negatively affects GABAergic transmission by modulating neuroligin2/gephyrin interaction Nat Commun doi 2014 10.1038/ncomms6066 PMC4197815 25297980 · DOI
  3. Bannai H Lévi S Schweizer C Inoue T Launey T Racine V Sibarita JB Mikoshiba K Activity-dependent tuning of inhibitory neurotransmission based on GABAAR diffusion dynamics Neuron 62 2009 670 682 19524526
  4. Bannai H Niwa F Sherwood MW Shrivastava AN Arizono M Miyamoto A Sugiura K Lévi S Bidirectional control of synaptic GABAAR clustering by glutamate and calcium Cell Rep 13 2015 2768 2780 26711343 PMC4700050
  5. Barberis A. (2019) Postsynaptic plasticity of GABAergic synapses. Neuropharmacology pii: S0028-3908(19)30169–8. doi: 10.1016/j.neuropharm. 31108109 · DOI
  6. Battaglia S, Renner M, Russeau M, Côme E, Tyagarajan SK, Lévi S. (2018) Activity-dependent inhibitory synapse scaling is determined by gephyrin phosphorylation and subsequent regulation of GABAA receptor diffusion. eNeuro 5.Pii:0203-17.2017. doi: 10.1523/ENEURO. PMC5780843 29379879 · DOI
  7. Biocca S Cattaneo A Intracellular immunization: antibody targeting to subcellular compartments Trends Cell Biol 5 1995 248 252 14732130
  8. Bossers K Wirz KT Meerhoff GF Essing AH van Dongen JW Houba P Kruse CG Verhaagen J Concerted changes in transcripts in the prefrontal cortex precede neuropathology in Alzheimer's disease Brain 133 2010 3699 3723 20889584
  9. Brady ML Jacob TC Synaptic localization of α5 GABA (a) receptors via gephyrin interaction regulates dendritic outgrowth and spine maturation Dev Neurobiol 75 2015 1241 1251 25663431 PMC5240477
  10. Buzsáki G Buhl DL Harris KD Csicsvari J Czéh B Morozov A Hippocampal network patterns of activity in the mouse Neuroscience 116 2003 201 211 12535953
  11. Cattaneo A, Chirichiella M. (2019) Targeting the post-translational proteome with intrabodies. Trends Biotechnol pii: S0167-7799(18)30319–6. doi: 10.1016/j.tibtech.2018.11.009. 30577991 · DOI
  12. Chen JL Villa KL Cha JW So PT Kubota Y Nedivi E Clustered dynamics of inhibitory synapses and dendritic spines in the adult neocortex Neuron 74 2012 361 373 22542188 PMC3340582
  13. Cherubini E Gaiarsa JL Ben-Ari Y GABA: an excitatory transmitter in early postnatal life Trends Neurosci 14 1991 515 519 1726341
  14. Chiu CQ Lur G Morse TM Carnevale NT Ellis-Davies GC Higley MJ Compartmentalization of GABAergic inhibition by dendritic spines Science 340 2013 759 762 23661763 PMC3752161
  15. Chiu CQ Barberis A Higley MJ Preserving the balance: diverse forms of long-term GABAergic synaptic plasticity Nat Rev Neurosci doi 2019 10.1038/s41583-019-0141-5 30837689 · DOI
  16. Choii G Ko J Gephyrin: a central GABAergic synapse organizer Exp Mol Med 47 2015 e158 10.1038/emm.2015.5 25882190 · DOI
  17. Choquet D Triller A The dynamic synapse Neuron 80 2013 691 703 24183020
  18. Costa JT Mele M Baptista MS Gomes JR Ruscher K Nobre RJ de Almeida LP Wieloch T Gephyrin cleavage in in vitro brain ischemia decreases GABAA receptor clustering and contributes to neuronal death Mol Neurobiol 53 2016 3513 3527 26093381
  19. Crosby KC Gookin SE Garcia JD Hahm KM Dell'Acqua ML Smith KR Nanoscale subsynaptic domains underlie the organization of the inhibitory synapse Cell Rep 26 2019 3284 3297 30893601 PMC6529211
  20. Davenport EC Pendolino V Kontou G McGee TP Sheehan DF López-Doménech G Farrant M Kittler JT An essential role for the tetraspanin LHFPL4 in the cell-type-specific targeting and clustering of synaptic GABAA receptors Cell Rep 21 2017 70 83 28978485 PMC5640807
  21. Dejanovic B Schwarz G Neuronal nitrioxide synthase-dependent S-nitrosylation of gephyrin regulates gephyrin clustering at GABAergic synapses J Neurosci 34 2014 7763 7768 24899700 PMC6608267
  22. Dejanovic B, Semtner M, Ebert S, Lamkemeyer T, Neuser F, Lüscher B, Meier JC, Schwarz G. (2014a) Palmitoylation of gephyrin controls receptor clustering and plasticity of GABAergic synapses. PLoS biol Jul 15;12(7):e1001908. doi: 10.1371/journal.pbio.1001908. PMC4099074 25025157 · DOI
  23. Dejanovic B Lal D Catarino CB Arjune S Belaidi AA Trucks H Vollmar C Surges R Exonic microdeletions of the gephyrin gene impair GABAergic synaptic inhibition in patients with idiopathic generalized epilepsy Neurobiol Dis 67 2014 88 96 24561070
  24. Dejanovic B Djémié T Grünewald N Suls A Kress V Hetsch F Craiu D Zemel M Simultaneous impairment of neuronal and metabolic function of mutated gephyrin in a patient with epileptic encephalopathy EMBO Mol Med 7 2015 1580 1594 26613940 PMC4693503
  25. Fang M Shen L Yin H Pan YM Wang L Chen D Xi ZQ Xiao Z Downregulation of gephyrin in temporal lobe epilepsy neurons in humans and a rat model Synapse 65 2011 1006 1014 21404332
  26. Feng G Tintrup H Kirsch J Nichol MC Kuhse J Betz H Sanes JR Dual requirement for gephyrin in glycine receptor clustering and molybdoenzyme activity Science 282 1998 1321 1324 9812897
  27. Fischer F Kneussel M Tintrup H Haverkamp S Rauen T Betz H Wässle H Reduced synaptic clustering of GABA and glycine receptors in the retina of the gephyrin null mutant mouse J Comp Neurol 427 2000 634 648 11056469
  28. Flores CE Nikonenko I Mendez P Fritschy JM Tyagarajan SK Muller D Activity-dependent inhibitory synapse remodeling through gephyrin phosphorylation Proc Natl Acad Sci U S A 112 2015 E65 E72 25535349 PMC4291629
  29. Förstera B Belaidi AA Jüttner R Bernert C Tsokos M Lehmann TN Horn P Dehnicke C Irregular RNA splicing curtails postsynaptic gephyrin in the cornu ammonis of patients with epilepsy Brain 133 2010 3778 3794 21071388
  30. Ghosh H Auguadri L Battaglia S Simone Thirouin Z Zemoura K Messner S Acuña MA Several posttranslational modifications act in concert to regulate gephyrin scaffolding and GABAergic transmission Nat Commun 7 2016 13365 10.1038/ncomms13365 27819299 PMC5103071 · DOI
  31. Giannone G Mondin M Grillo-Bosch D Tessier B Saint-Michel E Czöndör K Sainlos M Choquet D Neurexin-1β binding to neuroligin-1 triggers the preferential recruitment of PSD-95 versus gephyrin through tyrosine phosphorylation of neuroligin-1 Cell Rep 3 2013 1996 2007 23770246
  32. Giesemann T Schwarz G Nawrotzki R Berhörster K Rothkegel M Schlüter K Schrader N Schindelin H Complex formation between the postsynaptic scaffolding protein gephyrin, profilin, and Mena: a possible link to the microfilament system J Neurosci 23 2003 8330 8339 12967995 PMC6740687
  33. Gross GG Straub C Perez-Sanchez J Dempsey WP Junge JA Roberts RW Trinh le A Fraser SE An E3-ligase-based method for ablating inhibitory synapses, Nat Methods 13 2016 673 678 PMC5312699 27271196
  34. Grünewald N. Jan A. Salvatico C. Kress V. Renner M. Triller A. Specht C.G. Schwarz G. Sequences flanking the gephyrin-binding site of glyRβ tune receptor stabilization at synapses eNeuro 5 1 2018 Feb 19 10.1523/ENEURO.0042-17.2018 pii: ENEURO.0042-17.2018 PMC5818551 29464196 · DOI
  35. Haas KT, Compans B, Letellier M, Bartol TM, Grillo-Bosch D, Sejnowski TJ, Sainlos M, Choquet D et al. (2018) Pre–post synaptic alignment through neuroligin-1 tunes synaptic transmission efficiency. Elife 7, e31755. 10.7554/eLife.31755. pii. PMC6070337 30044218 · DOI · Paper page
  36. Hales CM Rees H Seyfried NT Dammer EB Duong DM Gearing M Montine TJ Troncoso JC Abnormal gephyrin immunoreactivity associated with Alzheimer disease pathologic changes J Neuropathol Exp Neurol 72 2013 1009 1015 24128675 PMC4037931
  37. Hanus C Ehrensperger MV Triller A Activity-dependent movements of postsynaptic scaffolds at inhibitory synapses J Neurosci 26 2006 4586 4595 16641238 PMC6674069
  38. Herweg J Schwarz G Splice-specific glycine receptor binding, folding, and phosphorylation of the scaffolding protein gephyrin J Biol Chem 287 2012 12645 12656 22351777 PMC3339950
  39. Hirata H Takahashi M Yamada K Ogino K The biological role of the glycinergic synapse in early zebrafish motility Neurosci Res 71 2011 1 11 21712054
  40. Horn ME Nicoll RA Somatostatin and parvalbumin inhibitory synapses onto hippocampal pyramidal neurons are regulated by distinct mechanisms Proc Natl Acad Sci U S A 115 2018 589 594 29295931 PMC5777005
  41. Hruska M Henderson N Le Marchand SJ Jafri H Dalva MB Synaptic nanomodules underlie the organization and plasticity of spine synapses Nat Neurosci 21 2018 671 682 29686261 PMC5920789
  42. Jacob TC Bogdanov YD Magnus C Saliba RS Kittler JT Haydon PG Moss SJ Gephyrin regulates the cell surface dynamics of synaptic GABAA receptors J Neurosci 25 2005 10469 10478 16280585 PMC6725824
  43. Jones MV Westbrook GL Desensitized states prolong GABAA channel responses to brief agonist pulses Neuron 15 1995 181 191 7542462
  44. Kim EY Schrader N Smolinsky B Bedet C Vannier C Schwarz G Schindelin H Deciphering the structural framework of glycine receptor anchoring by gephyrin EMBO J 25 2006 1385 1395 16511563 PMC1422172
  45. Kirsch J Malosio ML Wolters I Betz H Distribution of gephyrin transcripts in the adult and developing rat brain Eur J Neurosci 5 1993 1109 1117 8281317
  46. Kiss E Gorgas K Schlicksupp A Groß D Kins S Kirsch J Kuhse J Biphasic alteration of the inhibitory synapse scaffold protein gephyrin in early and late stages of an Alzheimer disease model Am J Pathol 86 2016 2279 2291 27423698
  47. Klausberger T Somogyi P Neuronal diversity and temporal dynamics: the unity of hippocampal circuit operations Science 321 2008 53 57 18599766 PMC4487503
  48. Kneussel M Brandstätter JH Gasnier B Feng G Sanes JR Betz H Gephyrin-independent clustering of postsynaptic GABA(A) receptor subtypes Mol Cell Neurosci 17 2001 973 982 11414787
  49. Knuesel I Zuellig RA Schaub MC Fritschy JM Alterations in dystrophin and utrophin expression parallel the reorganization of GABAergic synapses in a mouse model of temporal lobe epilepsy Eur J Neurosci 6 2001 1113 11124 11285009
  50. Kowalczyk S Winkelmann A Smolinsky B Förstera B Neundorf I Schwarz G Meier JC Direct binding of GABAA receptor β2 and β3 subunits to gephyrin Eur J Neurosci 37 2013 544 554 23205938
  51. Langosch D Hoch W Betz H The 93 kDa protein gephyrin and tubulin associated with the inhibitory glycine receptor are phosphorylated by an endogenous protein kinase FEBS Lett 298 1992 113 117 1312018
  52. Legendre P Muller E Badiu CI Meier J Vannier C Triller A Desensitization of homomeric alpha1 glycine receptor increases with receptor density Mol Pharmacol 62 2002 817 827 12237328
  53. Lencz T Lambert C DeRosse P Burdick KE Morgan TV Kane JM Kucherlapati R Malhotra AK Runs of homozygosity reveal highly penetrant recessive loci in schizophrenia Proc Natl Acad Sci U S A 104 2007 19942 19947 18077426 PMC2148402
  54. Liang J López-Valdés HE Martínez-Coria H Lindemeyer AK Shen Y Shao XM Olsen RW Dihydromyricetin ameliorates behavioral deficits and reverses neuropathology of transgenic mouse models of Alzheimer's disease Neurochem Res 39 2014 1171 1181 24728903
  55. Limon A Reyes-Ruiz JM Miledi R Loss of functional GABA(A) receptors in the Alzheimer diseased brain Proc Natl Acad Sci U S A 109 2012 10071 10076 22691495 PMC3382476
  56. Lionel AC Vaags AK Sato D Gazzellone MJ Mitchell EB Chen HY Costain G Walker S Rare exonic deletions implicate the synaptic organizer Gephyrin (GPHN) in risk for autism, schizophrenia and seizures Hum Mol Genet 22 2013 2055 2066 23393157
  57. Lushnikova I Skibo G Muller D Nikonenko I Excitatory synaptic activity is associated with a rapid structural plasticity of inhibitory synapses on hippocampal CA1 pyramidal cells Neuropharmacology 60 2011 757 764 21187106
  58. MacGillavry HD Kerr JM Blanpied TA Lateral organization of the postsynaptic density Mol Cell Neurosci 48 2011 321 331 21920440 PMC3216044
  59. MacGillavry HD Song Y Raghavachari S Blanpied TA Nanoscale scaffolding domains within the postsynaptic density concentrate synaptic AMPA receptors Neuron 78 2013 615 622 23719161 PMC3668352
  60. Marchionni I Kasap Z Mozrzymas JW Sieghart W Cherubini E Zacchi P New insights on the role of gephyrin in regulating both phasic and tonic GABAergic inhibition in rat hippocampal neurons in culture Neuroscience 164 2009 552 562 19660531
  61. Maric HM Mukherjee J Tretter V Moss SJ Schindelin H Gephyrin-mediated γ-aminobutyric acid type A and glycine receptor clustering relies on a common binding site J Biol Chem 286 2011 42105 42114 22006921 PMC3234978
  62. Maric HM Kasaragod VB Hausrat TJ Kneussel M Tretter V Strømgaard K Schindelin H Molecular basis of the alternative recruitment of GABA(A) versus glycine receptors through gephyrin Nat Commun 5 2014 5767 10.1038/ncomms6767 25531214 · DOI
  63. Maric HM Hausrat TJ Neubert F Dalby NO Doose S Sauer M Kneussel M Strømgaard K Gephyrin-binding peptides visualize postsynaptic sites and modulate neurotransmission Nat Chem Biol 13 2017 153 160 27893705
  64. Martenson JS, Yamasaki T, Chaudhury NH, Albrecht D, Tomita S. (2017) Assembly rules for GABAA receptor complexes in the brain. Elife 6. Pii: e30826. doi: 10.7554/eLife.27443. PMC5577914 28816653 · DOI
  65. Melchionna T Cattaneo A A protein silencing switch by ligand-induced proteasome-targeting intrabodies J Mol Biol 374 2007 641 654 17950312
  66. Moss SJ Smart TG Constructing inhibitory synapses Nat Rev Neurosci 2 2001 240 250 11283747
  67. Mukherjee J Kretschmannova K Gouzer G Maric HM Ramsden S Tretter V Harvey K Davies PA The residence time of GABA(A)Rs at inhibitory synapses is determined by direct binding of the receptor α1 subunit to gephyrin J Neurosci 31 2011 14677 14687 21994384 PMC3202462
  68. Nair D Hosy E Petersen JD Constals A Giannone G Choquet D Sibarita JB Super-resolution imaging reveals that AMPA receptors inside synapses are dynamically organized in nanodomains regulated by PSD95 J Neurosci 33 2013 13204 13224 23926273 PMC6619720
  69. Nawrotzki R Islinger M Vogel I Völkl A Kirsch J Expression and subcellular distribution of gephyrin in non-neuronal tissues and cells Histochem Cell Biol 137 2012 471 482 22270318
  70. Newpher TM Ehlers MD Glutamate receptor dynamics in dendritic microdomains Neuron 58 2008 472 497 18498731 PMC2572138
  71. Nguyen QA, Horn ME, Nicoll RA (2016) Distinct roles for extracellular and intracellular domains in neuroligin function at inhibitory synapses. Elife Nov 2;5. Pii: e19236. doi: 10.7554/eLife.19236. PMC5098909 27805570 · DOI
  72. Niwa F Bannai H Arizono M Fukatsu K Triller A Mikoshiba K Gephyrin-independent GABA(A)R mobility and clustering during plasticity PLoS One 7 2012 e36148 10.1371/journal.pone.0036148 PMC3338568 22563445 · DOI
  73. Nusser Z. Cull-Candy S. Farrant M. Differences in synaptic GABA(A) receptor number underlie variation in GABA mini amplitude Neuron 19 1997 697 709 9331359
  74. Oh WC Lutzu S Castillo PE Kwon HB De novo synaptogenesis induced by GABA in the developing mouse cortex Science 353 2016 1037 1040 27516412 PMC5104171
  75. Okabe S Molecular anatomy of the postsynaptic density Mol Cell Neurosci 34 2007 503 518 17321751
  76. Panzanelli P, Gunn BG, Schlatter MC, Benke D, Tyagarajan SK, Scheiffele P, Belelli D, Lambert JJ et al. Distinct mechanisms regulate GABAA receptor and gephyrin clustering at perisomatic and axo-axonic synapses on CA1 pyramidal cells. J Physiol 589:4959–4980. PMC3224886 21825022
  77. Papadopoulos T Korte M Eulenburg V Kubota H Retiounskaia M Harvey RJ Harvey K O'Sullivan GA Impaired GABAergic transmission and altered hippocampal synaptic plasticity in collybistin-deficient mice EMBO J 26 2007 3888 3899 17690689 PMC1994120
  78. Patrizio A Renner M Pizzarelli R Triller A Specht CG Alpha subunit-dependent glycine receptor clustering and regulation of synaptic receptor numbers Sci Rep 7 1 2017 10899 10.1038/s41598-017-11264-3 28883437 PMC5589798 · DOI
  79. Pennacchietti F Vascon S Nieus T Rosillo C Das S Tyagarajan SK Diaspro A Del Bue A Nanoscale molecular reorganization of the inhibitory postsynaptic density is a determinant of GABAergic synaptic potentiation J Neurosci 37 2017 1747 1756 28073939 PMC6589977
  80. Petrini EM, Barberis A. (2014) Diffusion dynamics of synaptic molecules during inhibitory postsynaptic plasticity. Front cell Neurosci Sep 23;8:300. doi: 10.3389/fncel. PMC4171989 25294987 · DOI
  81. Petrini EM Ravasenga T Hausrat TJ Iurilli G Olcese U Racine V Sibarita JB Jacob TC Synaptic recruitment of gephyrin regulates surface GABAA receptor dynamics for the expression of inhibitory LTP Nat Comm 5 2014 3921 10.1038/ncomms4921 PMC4059940 24894704 · DOI
  82. Pfeiffer F Graham D Betz H Purification by affinity chromatography of the glycine receptor of rat spinal cord J Biol Chem 257 1982 9389 9393 6286620
  83. Poulopoulos A Aramuni G Meyer G Soykan T Hoon M Papadopoulos T Zhang M Paarmann I Neuroligin 2 drives postsynaptic assembly at perisomatic inhibitory synapses through gephyrin and collybistin Neuron 63 2009 628 642 19755106
  84. Prior P Schmitt B Grenningloh G Pribilla I Multhaup G Beyreuther K Maulet Y Werner P Primary structure and alternative splice variants of gephyrin, a putative glycine receptor-tubulin linker protein Neuron 8 1992 1161 1170 1319186
  85. Ramming M Kins S Werner N Hermann A Betz H Kirsch J Diversity and phylogeny of gephyrin: tissue-specific splice variants, gene structure, and sequence similarities to molybdenum cofactor-synthesizing and cytoskeleton-associated proteins Proc Natl Acad Sci U S A 97 2000 10266 10271 10963686 PMC27865
  86. Raychaudhuri S, Plenge RM, Rossin EJ, Ng AC; International Schizophrenia Consortium, Purcell SM, Sklar P, Scolnick EM et al Identifying relationships among genomic disease regions: predicting genes at pathogenic SNP associations and rare deletions PLoS Genet 5 2009 e1000534 10.1371/journal.pgen.1000534 PMC2694358 19557189 · DOI
  87. Sabatini DM Barrow RK Blackshaw S Burnett PE Lai MM Field ME Bahr BA Kirsch J Interaction of RAFT1 with gephyrinrequired for rapamycin-sensitive signaling Science 284 1999 1161 1164 10325225
  88. Sander B Tria G Shkumatov AV Kim EY Grossmann JG Tessmer I Svergun DI Schindelin H Structural characterization of gephyrin by AFM and SAXS reveals a mixture of compact and extended states Acta Crystallogr D Biol Crystallogr 69 2013 2050 2060 24100323
  89. Schwarz G Schrader N Mendel R Hechet HJ Schindelin H Cristal structure of human gephyrin and plant Cnx1 G domains: comparative analysis and functional implications J Mol Biol 312 2001 405 418 11554796
  90. Shen ZC Wu PF Wang F Xia ZX Deng Q Nie TL Zhang SQ Zheng HL Gephyrin palmitoylation in basolateral amygdala mediates the anxiolytic action of benzodiazepine Biol Psychiatry 85 2019 202 213 30454851
  91. Sheng M Kim E The postsynaptic organization of synapses Cold Spring Harb Perspect Biol doi 2011 10.1101/cshperspect.a005678 PMC3225953 22046028 · DOI · Paper page
  92. Smith KR Davenport EC Wei J Li X Pathania M Vaccaro V Yan Z Kittler JT GIT1 and βPIX are essential for GABA(A) receptor synaptic stability and inhibitory neurotransmission Cell Rep 9 2014 298 310 25284783 PMC4536293
  93. Sola M Kneussel M Heck IS Betz H Weissenhorn W X-ray crystal structures of the trimeric N-terminal domain of gephyrin J Biol Chem 276 2001 25294 25301 11325967
  94. Sola M Bavro VN Timmins J Franz T Ricard-Blum S Schoehn G Ruigrok RW Paarmann I Structural basis of dynamic glycine receptor clustering by gephyrin EMBO J 23 2004 2510 2519 15201864 PMC449768
  95. Specht CG. (2019) Fractional occupancy of synaptic binding sites and the molecular. Plasticity of inhibitory synapses. Neuropharmacology pii: S0028-3908(19)30007–3. doi: 10.1016/j.neuropharm.2019.01.008. 30648560 · DOI
  96. Specht CG Izeddin I Rodriguez PC El Beheiry M Rostaing P Darzacq X Dahan M Triller A Quantitative nanoscopy of inhibitory synapses: counting gephyrin molecules and receptor binding sites Neuron 79 2013 308 321 23889935
  97. Thompson AJ Lester HA Lummis SC The structural basis of function in Cys-loop receptors Q Rev Biophys 43 2010 449 499 10.1017/S0033583510000168 20849671 · DOI
  98. Tretter V, Mukherjee J, Maric HM, Schindelin H, Sieghart W, Moss SJ. (2012) Gephyrin the enigmatic organizer at GABAergic synapses. Front Cell Neurosci May 15;6:23. doi: 10.3389/fncel.2012.00023. PMC3351755 22615685 · DOI
  99. Tyagarajan SK Fritschy JM Gephyrin: a master regulator of neuronal function? Nat Rev Neurosci 15 2014 141 156 24552784
  100. Tyagarajan SK Ghosh H Yévenes GE Nikonenko I Ebeling C Schwerdel C Sidler C Zeilhofer HU Regulation of GABAergic synapse formation and plasticity by GSK3beta-dependent phosphorylation of gephyrin Proc Natl Acad Sci U S A 108 2011 379 384 21173228 PMC3017200
  101. Tyagarajan SK Ghosh H Yévenes GE Imanishi SY Zeilhofer HU Gerrits B Fritschy JM Extracellular signal-regulated kinase and glycogen synthase kinase 3β regulate gephyrin postsynaptic aggregation and GABAergic synaptic function in a calpain-dependent mechanism J Biol Chem 288 2013 9634 9647 23408424 PMC3617267
  102. Um JW Choii G Park D Kim D Jeon S Kang H Mori T Papadopoulos T IQ motif and SEC7 domain-containing protein 3 (IQSEC3) interacts with gephyrin to promote inhibitory synapse formation J Biol Chem 291 2016 10119 10130 27002143 PMC4858964
  103. van Versendaal D Rajendran R Saiepour MH Klooster J Smit-Rigter L Sommeijer JP De Zeeuw CI Hofer SB Elimination of inhibitory synapses is a major component of adult ocular dominance plasticity Neuron 74 2012 374 383 22542189
  104. van Zundert B Castro P Aguayo LG Glycinergic and GABAergic synaptic transmission are differentially affected by gephyrin in spinal neurons Brain Res 1050 2005 40 47 15963957
  105. Varley ZK Pizzarelli R Antonelli R Stancheva SH Kneussel M Cherubini E Zacchi P Gephyrin regulates GABAergic and glutamatergic synaptic transmission in hippocampal cell cultures J Biol Chem 286 2011 20942 20951 21507951 PMC3121485
  106. Villa KL Berry KP Subramanian J Cha JW Oh WC Kwon HB Kubota Y So PT Nedivi E Inhibitory synapses are repeatedly assembled and removed at persistent sites in vivo Neuron 89 2016 756 769 26853302 PMC4760889
  107. Visintin M Tse E Axelson H Rabbitts TH Cattaneo A Selection of antibodies for intracellular function using a two-hybrid in vivo system Proc Natl Acad Sci U S A 96 1999 11723 11728 10518517 PMC18353
  108. Yamasaki T Hoyos-Ramirez E Martenson JS Morimoto-Tomita M Tomita S GARLH family proteins stabilize GABAA receptors at synapses Neuron 93 2017 1138 1152 28279354 PMC5347473
  109. Yu JY, Pearl PL. (2013) Metabolic causes of epileptic encephalopathy. Epilepsy Res Treat:124934. doi: 10.1155/2013/124934. PMC3674738 23762547 · DOI
  110. Yu W Jiang M Miralles CP Li RW Chen G de Blas AL Gephyrin clustering is required for the stability of GABAergic synapses Mol Cell Neurosci 36 2007 484 500 17916433 PMC2464357
  111. Zacchi P Dreosti E Visintin M Moretto-Zita M Marchionni I Cannistraci I Kasap Z Betz H Gephyrin selective intrabodies as a new strategy for studying inhibitory receptor clustering J Mol Neurosci 34 2008 141 148 18008186 PMC2758390
  112. Zacchi P, Antonelli R, Cherubini E. (2014) Gephyrin phosphorylation in the functional organization and plasticity of GABAergic synapses. Front cell Neurosci Apr 9;8:103. doi: 10.3389/fncel.2014.00103. PMC3988358 24782709 · DOI

Cited by

Sorted by citations

Authors
Pizzarelli, R., Griguoli, M., Zacchi, P., Petrini, E. M., Barberis, A., Cattaneo, A., & Cherubini, E.
Affiliations
  • European Brain Research Institute (IT)
  • University of Trieste (IT)
  • Italian Institute of Technology (IT)
  • Scuola Normale Superiore (IT)
  • Scuola Internazionale Superiore di Studi Avanzati (IT)
Corresponding author
Cherubini, Enrico
ORCID
Venue
Neuroscience
Publisher
Elsevier BV
Published
2020-07
Volume
439
Pages
125-136
ISSN
0306-4522 (ISSN-L)
DOI
10.1016/j.neuroscience.2019.07.036
PMC
PMC7351109
OpenAlex
W2966533410
Cited by
69
References
5
Citations by year
2026: 9 · 2025: 12 · 2024: 8 · 2023: 6 · 2022: 11 · 2021: 13 · 2020: 9 · 2019: 1
FWCI
1.13
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuroscience (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • ArTS Archivio della ricerca di Trieste (University of Trieste https://www.units.it/) (submittedVersion, cc-by-nc-nd)
  • Scuola Normale Superiore di Pisa (submittedVersion, cc-by-nc-nd)
Funders
Fondazione Telethon
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 › Receptor Mechanisms and Signaling
Keywords
gephyrin, GABAergic inhibition, inhibitory synapses, synaptic scaffolding, cytoskeleton, post-translational modification, synaptic plasticity, autism spectrum disorder, schizophrenia, temporal lobe epilepsy, Alzheimer's disease, GABAergic neurotransmission
MeSH terms
Carrier Proteins, Humans, Membrane Proteins, Receptors, GABA-A, Synapses

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.

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 ›

Are you an author, or do you see a problem with this page? Request a review