Presynaptic NMDA receptors facilitate short-term plasticity and BDNF release at hippocampal mossy fiber synapses

Neurotransmitter release is a highly controlled process by which synapses can critically regulate information transfer within neural circuits. While presynaptic receptors -typically activated by neurotransmitters and modulated by neuromodulators- provide a powerful way of fine tuning synaptic function, their contribution to activity-dependent changes in transmitter release remains poorly understood. Here, we report that presynaptic NMDA receptors (preNMDARs) at hippocampal mossy fiber boutons can be activated by physiologically relevant patterns of activity and selectively enhance short-term synaptic plasticity at mossy fiber inputs onto CA3 pyramidal cells and mossy cells, but not onto inhibitory interneurons. Moreover, preNMDARs facilitate brain-derived neurotrophic factor (BDNF) release and contribute to presynaptic calcium rise. Taken together, our results indicate that preNMDARs, by increasing presynaptic calcium, fine tune mossy fiber neurotransmission and can control information transfer during dentate granule cell burst activity that normally occur in vivo.