Abstract
During development, activity-dependent synaptic plasticity refines neuronal networks with high precision. For example, spontaneous activity helps sorting synaptic inputs with similar activity patterns into clusters to enhance neuronal computations in the mature brain. Here, we show that TrkB activation and postsynaptic brain-derived neurotrophic factor (BDNF) are required for synaptic clustering in developing hippocampal neurons. Moreover, BDNF and TrkB modulate transmission at synapses depending on their clustering state,indicating that endogenous BDNF/TrkB signaling stabilizes locally synchronized synapses. Togetherwith our previous data on proBDNF/p75NTR signaling, these findings suggest a push-pull plasticity mechanism for synaptic clustering: BDNF stabilizes clustered synapses while proBDNF downregulates out-of-sync synapses. This idea is supported by our observation that synaptic clustering requires matrix-metalloproteinase-9 activity, a proBDNF-to-BDNF converting enzyme. Finally, NMDA receptor activation mediates out-of-sync depression upstream of proBDNF signaling. Together, these data delineate an efficient plasticity mechanism where proBDNF and mature BDNF establish synaptic clustering through antagonistic modulation of synaptic transmission.
Highlights
Neurons in the developing brain generate precisely connected networks already before the senses become active
Probing the effect of brain-derived neurotrophic factor (BDNF) on single synapses, we provide evidence for a push-pull plasticity mechanism driven by spontaneous activity and NMDA receptor activation, where BDNF/ tropomyosin-related kinase receptor B (TrkB) signaling strengthens clustered synapses, proBDNF/ p75NTR signaling depresses out-of-sync synapses, and MMP9mediated proBDNF-to-BDNF conversion occurs at clustered synapses to efficiently sort synaptic inputs into correlated clusters along dendrites
Because proBDNF and mature BDNF have antagonistic roles in cellular survival and synaptic function
Summary
Neurons in the developing brain generate precisely connected networks already before the senses become active. At all stages of brain development, neurotrophins play a pivotal role for generating precisely connected networks. BDNF regulates dendritic growth in an activity-dependent manner (Lai et al, 2012; McAllister et al, 1996); it promotes formation, unsilencing, and maturation of excitatory and inhibitory synapses (Cabezas and Buno, 2011; Huang et al, 1999; Mohajerani et al, 2007; Vicario-Abejon et al, 1998); and it contributes to the refinement of neuronal connections (Cabelli et al, 1995, 1997; Choo et al, 2017; review: Schinder and Poo, 2000)
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