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 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 LTP_pre induction. Our findings reveal a novel framework of presynaptic plasticity that radically differs from traditional models of postsynaptic plasticity.

人们认为，hebbian可塑性需要谷氨酸信号传导。我们显示，海马突触前长期增强作用（LTP _pre）并非如此，这表示为递质释放概率（P _r）的增加。我们发现LTP _pre可以通过在没有谷氨酸信号的情况下配对突触前和突触后突触来诱导。LTP_预诱导涉及逆向一氧化氮信号传导的非经典机制，该机制由来自L型电压门控Ca ²⁺通道的Ca ²⁺流入触发，而不是突触后NMDA受体（NMDARs）触发，不需要谷氨酸释放。发生谷氨酸释放时，它会降低P _r通过激活突触前NMDAR，并促进突触前长期抑郁。因此，P _r的净变化取决于两个相反的因素：1）Hebbian活性增加P _r，2）谷氨酸释放减少P _r。因此，Hebbian活动期间的释放失败会促进LTP_预诱导。我们的发现揭示了一种新型的突触前可塑性框架，该框架与传统的突触后可塑性模型完全不同。