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TRAF6 controls excitatory spinogenesis and excitation-inhibition balance though binding neuroplastin

Vemula, Sampath Kumar and Malci, Ayse and Junge, Lennart and Lehmann, Anne-Christin and Rama, Ramya and Hradsky, Johannes and Matute, Ricardo A. and Naumann, Michael and Kreutz, Michael R. and Seidenbecher, Constanze I. and Gundelfinger, Eckart D. and Herrera-Molina, Rodrigo and Weber, André and Prigge, Matthias (2019) TRAF6 controls excitatory spinogenesis and excitation-inhibition balance though binding neuroplastin. . (Unpublished)

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Cell-autonomous mechanisms of early synaptogenesis and their impact on the excitatory-inhibitory brain balance are poorly understood. By analyzing binding motifs in cytoplasmic regions of synaptogenic cell adhesion molecules, we identified a tumor necrosis factor receptor-associated factor 6 (TRAF6) binding motif in neuroplastin. Three-dimensional molecular modelling and biochemical approaches identified amino acids in neuroplastin binding the TRAF-C of TRAF6 with micromolar affinity. TRAF6 is required for spinogenesis and its association with neuroplastin fostered formation of new postsynapses in young hippocampal neurons. Also, TRAF6 is strictly necessary to restore failed spinogenesis in neuroplastin-deficient neurons via neuroplastin expression. These features are independent from neuroplastin extracellular adhesive properties or its known interaction with plasma-membrane Ca2+ ATPases. Furthermore, TRAF6-mediated neuroplastin-dependent spinogenesis determinates the excitatory synapse density and in turn the balance of E-I synapses in mature neurons. These findings provide a highly specific cell-encoded mechanism for early synaptogenesis crucial for neuronal connectivity.

Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription Paper
Vemula, Sampath Kumar0000-0002-4052-4218
Matute, Ricardo A.0000-0002-0644-3799
Kreutz, Michael R.0000-0003-0575-6950
Seidenbecher, Constanze I.0000-0002-7433-2716
Gundelfinger, Eckart D.0000-0001-9377-7414
Herrera-Molina, Rodrigo0000-0001-9597-5131
Alternate Title:TRAF6 controls spinogenesis instructing synapse density and neuronal activity through binding neuroplastin
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. bioRxiv preprint first posted online Sep. 14, 2019. We thank to Dr. Dirk Montag for kindly providing Nptn-/- mice for breading and to Kathrin Pohlmann for her technical work. S.K.V. thanks to the GRK 1167. A.M. thanks the federal state Saxony-Anhalt and the European Structural and Investment Funds (ESF, 2014-2020), project number ZS/2016/08/80645. R.A.M. thanks the FONDECYT Grant No. 1181260. R.H-M., C.I.S., and E.D.G. thanks to SFB 854 and BMBF 01DN17002. Author Contributions: S.K.V. and A.M. conducted most of the experiments. L.J. conducted PMCA experiments. A-C.L. and R.R. made constructs. J.H. and M.K. conducted SPR experiments and data interpretation. R.A.M. conducted in silico modelling. M.N., C.I.S., E.D.G. concept and data interpretation. R.H.M. concept, conducted experiments, data interpretation, wrote manuscript draft. All authors contributed to the manuscript final version.
Funding AgencyGrant Number
Leibniz Institute for NeurobiologyGRK 1167
European Structural and Investment FundsZS/2016/08/80645
Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT)1181260
Deutsche Forschungsgemeinschaft (DFG)SFB 854
Bundesministerium für Bildung und Forschung (BMBF)01DN17002
Subject Keywords:Synapse formation, excitatory spinogenesis, TRAF6, E-I synapse balance, neuroplastin, dendritic protrusion, neuronal connectivity
Record Number:CaltechAUTHORS:20190916-125446568
Persistent URL:
Official Citation:TRAF6 controls excitatory spinogenesis and excitation-inhibition balance through binding neuroplastin. Sampath Kumar Vemula, Ayse Malci, Lennart Junge, Anne-Christin Lehmann, Ramya Rama, Johannes Hradsky, Ricardo A. Matute, Michael Naumann, Michael R. Kreutz, Constanze I. Seidenbecher, Eckart D. Gundelfinger, Rodrigo Herrera-Molina. bioRxiv 768341; doi:
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:98657
Deposited By: Tony Diaz
Deposited On:16 Sep 2019 21:05
Last Modified:16 Nov 2021 17:40

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