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 (LTP(pre)), which is expressed as an increase in transmitter release probability (P(r)). We find that LTP(pre) can be induced by pairing pre- and postsynaptic spiking in the absence of glutamate signalling. LTP(pre) induction involves a non-canonical mechanism of retrograde nitric oxide signalling, which is triggered by Ca(2+) influx from L-type voltage-gated Ca(2+) 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 LTP(pre) induction. Our findings reveal a novel framework of presynaptic plasticity that radically differs from traditional models of postsynaptic plasticity.