Glutamate is required for depression but not potentiation of long-term presynaptic function

Hebbian plasticity is thought to require glutamate signalling. We show this is not the case for hippocampal presynaptic long-term potentiation (LTPpre), which is expressed as an increase in transmitter release probability (P-r). We find that LTPpre can be induced by pairing pre- and postsynaptic spiking in the absence of glutamate signalling. LTPpre induction involves a noncanonical mechanism of retrograde nitric oxide signalling, which is triggered by Ca2+ influx from L-type voltage-gated Ca2+ channels, not postsynaptic NMDA receptors (NMDARs), and does not require glutamate release. When glutamate release occurs, it decreases P-r by activating presynaptic NMDARs, and promotes presynaptic long-term depression. Net changes in P-r, therefore, depend on two opposing factors: (1) Hebbian activity, which increases P-r, and (2) glutamate release, which decreases P-r. Accordingly, release failures during Hebbian activity promote LTPpre induction. Our findings reveal a novel framework of presynaptic plasticity that radically differs from traditional models of postsynaptic plasticity.