TRAF6 controls excitatory spinogenesis and excitation-inhibition balance though binding neuroplastin
Abstract
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.
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.Attached Files
Submitted - 768341v4.full.pdf
Supplemental Material - media-1.pdf
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Additional details
- Alternative title
- TRAF6 controls spinogenesis instructing synapse density and neuronal activity through binding neuroplastin
- Eprint ID
- 98657
- Resolver ID
- CaltechAUTHORS:20190916-125446568
- GRK 1167
- Leibniz Institute for Neurobiology
- Saxony-Anhalt
- ZS/2016/08/80645
- European Structural and Investment Funds
- 1181260
- Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT)
- SFB 854
- Deutsche Forschungsgemeinschaft (DFG)
- 01DN17002
- Bundesministerium für Bildung und Forschung (BMBF)
- Created
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2019-09-16Created from EPrint's datestamp field
- Updated
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2021-11-16Created from EPrint's last_modified field