BDNF mobilizes synaptic vesicles and enhances synapse formation by disrupting cadherin–β-catenin interactions

Abstract

Neurons of the vertebrate central nervous system have the capacity to modify synapse number, morphology, and efficacy in response to activity. Some of these functions can be attributed to activity-induced synthesis and secretion of the neurotrophin brain-derived neurotrophic factor (BDNF); however, the molecular mechanisms by which BDNF mediates these events are still not well understood. Using time-lapse confocal analysis, we show that BDNF mobilizes synaptic vesicles at existing synapses, resulting in small clusters of synaptic vesicles “splitting” away from synaptic sites. We demonstrate that BDNF's ability to mobilize synaptic vesicle clusters depends on the dissociation of cadherin–β-catenin adhesion complexes that occurs after tyrosine phosphorylation of β-catenin. Artificially maintaining cadherin–β-catenin complexes in the presence of BDNF abolishes the BDNF-mediated enhancement of synaptic vesicle mobility, as well as the longer-term BDNF-mediated increase in synapse number. Together, this data demonstrates that the disruption of cadherin–β-catenin complexes is an important molecular event through which BDNF increases synapse density in cultured hippocampal neurons.

Axonal ribosomes and mRNAs associate with fragile X granules in adult rodent and human brains

“…Therefore, we propose that FXGs regulate local translation in the mature axonal arbour, likely in the context of adult plasticity. In support of such a role, mammalian brain axons contain transcripts encoding the plasticity-related proteins b-catenin, a regulator of synaptic vesicle distribution (48,49) and OMP, which modulates odorinduced signal transduction (50)(51)(52)(53).…”

Cognitive flexibility and long-term depression (LTD) are impaired following β-catenin stabilization in vivo

“…In vitro evidence demonstrates that β-catenin/cadherin interactions are dynamically regulated in response to activity (10,11), allowing β-catenin to modify cadherin stability during different forms of synaptic plasticity. Enhanced neural activity increases β-catenin/cadherin interaction in dendritic spines, stabilizing cadherin at synapses (10).…”

Catenins: playing both sides of the synapse

“…Application of BDNF to neurons enhances synaptic transmission and induces synapse sprouting. It was recently discovered that BDNF promotes splitting of synaptic vesicle clusters, and this activity depends on dissociation of cadherin-β-catenin complexes [18]. Tyrosine phosphorylation of β-catenin is required for dissociation from cadherins [22], and when this is blocked BDNF-mediated vesicle cluster splitting and synapse formation is prevented.…”

“…Finally, endogenous α-N-catenin, the neuronal form of α-catenin, is found at synapses [11], and EGFP-tagged α-Ncatenin localizes to dendritic spines and weakly to axons [17] similar to that of EGFP-tagged β-catenin. Like other cell-cell junctions, catenin localization at synapses is believed to be largely cadherin-driven [11], and evidence suggests that cadherin-catenin complexes are formed on both sides of the synapse [11,[16][17][18][19] (a model for catenin function in synapses is shown in Figure 2). However, as described earlier, there are clear structural and functional differences between the presynaptic and postsynaptic compartment.…”