Journal
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
Volume 8, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fcell.2020.579513
Keywords
dendritic protrusion; neuroplastin; E-I synapse balance; TRAF6; excitatory spinogenesis; synapse formation; neuronal connectivity
Categories
Funding
- DFG [GRK 1167, SFB 854]
- federal state of Saxony-Anhalt
- European Structural and Investment Funds (ESF, 2014-2020) [ZS/2016/08/80645]
- FONDECYT [1181260]
- Leibniz Association [SheLi J28/2017]
- DAAD [57514679]
- BMBF [01DN17002]
- ABINEP graduate school
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Correct brain wiring depends on reliable synapse formation. Nevertheless, signaling codes promoting synaptogenesis are not fully understood. Here, we report a spinogenic mechanism that operates during neuronal development and is based on the interaction of tumor necrosis factor receptor-associated factor 6 (TRAF6) with the synaptic cell adhesion molecule neuroplastin. The interaction between these proteins was predicted in silico and verified by co-immunoprecipitation in extracts from rat brain and co-transfected HEK cells. Binding assays show physical interaction between neuroplastin's C-terminus and the TRAF-C domain of TRAF6 with a K-d value of 88 mu M. As the two proteins co-localize in primordial dendritic protrusions, we used young cultures of rat and mouse as well as neuroplastin-deficient mouse neurons and showed with mutagenesis, knock-down, and pharmacological blockade that TRAF6 is required by neuroplastin to promote early spinogenesis during in vitro days 6-9, but not later. Time-framed TRAF6 blockade during days 6-9 reduced mEPSC amplitude, number of postsynaptic sites, synapse density and neuronal activity as neurons mature. Our data unravel a new molecular liaison that may emerge during a specific window of the neuronal development to determine excitatory synapse density in the rodent brain.
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