NMDA-Dependent Switch of proBDNF Actions on Developing GABAergic Synapses

The brain-derived neurotrophic factor (BDNF) has emerged as an important messenger for activity-dependent development of neuronal network. Recent findings have suggested that a significant proportion of BDNF can be secreted as a precursor (proBDNF) and cleaved by extracellular proteases to yield the mature form. While the actions of proBDNF on maturation and plasticity of excitatory synapses have been studied, the effect of the precursor on developing GABAergic synapses remains largely unknown. Here, we show that regulated secretion of proBDNF exerts a bidirectional control of GABAergic synaptic activity with NMDA receptors driving the polarity of the plasticity. When NMDA receptors are activated during ongoing synaptic activity, regulated Ca2+-dependent secretion of proBDNF signals via p75(NTR) to depress GABAergic synaptic activity, while in the absence of NMDA receptors activation, secreted proBDNF induces a p75(NTR)-dependent potentiation of GABAergic synaptic activity. These results revealed a new function for proBDNF-p75(NTR) signaling in synaptic plasticity and a novel mechanism by which synaptic activity can modulate the development of GABAergic synaptic connections.