Abstract
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 Kd value of 88 μM. 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.
Highlights
Synaptogenesis is a timely coordinated cellular process, which sets up the neuronal connectivity essential for information flow and processing in healthy brains (McAllister, 2007; Sudhof, 2008, 2017)
As tumor necrosis factor receptor-associated factor 6 (TRAF6) mediated filopodia formation by neuroplastin in Human embryonic kidney (HEK) cells, we studied the involvement of the two proteins in the formation of dendritic protrusions, which act as precursors of spines in mature neurons (Ziv and Smith, 1996; McClelland et al, 2010)
Our findings uncover a novel function for TRAF6 in neuronal development and link it to neuroplastin – shown to be relevant in vivo for defining numbers of excitatory synapses and balancing excitation and inhibition in the brain
Summary
Synaptogenesis is a timely coordinated cellular process, which sets up the neuronal connectivity essential for information flow and processing in healthy brains (McAllister, 2007; Sudhof, 2008, 2017). There is limited knowledge on how such molecules organize the formation of primordial glutamatergic synapses and it has not been fully appreciated how signaling events occurring during the development of neurons contribute to the establishment of future connectivity yielding correct synapse density in the brain (Yoshihara et al, 2009; Sudhof, 2017). Inducible elimination of neuroplastin expression in fully developed adult mice does not modify the number of hippocampal excitatory synapses (Bhattacharya et al, 2017). It remains unknown how and when neuroplastin participates in synaptogenesis necessary for the proper establishment of synapse density, synaptic transmission, and neuronal activity
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