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

Abstract

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 (Pr). We find that LTPpre can be induced by pairing pre- and postsynaptic spiking in the absence of glutamate signalling. LTPpre 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 Pr by activating presynaptic NMDARs, and promotes presynaptic long-term depression. Net changes in Pr, therefore, depend on two opposing factors: (1) Hebbian activity, which increases Pr, and (2) glutamate release, which decreases Pr. 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.

Towards resolving the presynaptic NMDA receptor debate

“…1) [17]. Recently, Padamsey et al [39] demonstrated that GluN1 deletion in CA3 abolished presynaptic LTD, strengthening the evidence for preNMDARs underpinning CA3-CA1 LTD.…”

Illuminating Relationships Between the Pre- and Post-synapse

“…For example, one highly reproduced finding that mirrors the presynaptic structural diversity of synapses is that the probability of neurotransmitter release [P(r)] at central synapses is highly variable. The diversity of P(r) has been measured using a variety of methods including the progressive block by the use-dependent NMDA receptor (NMDAR) antagonist MK-801 (Hessler et al, 1993;Rosenmund et al, 1993), the activity-dependent uptake of styryl dye (Murthy et al, 1997;Sanderson et al, 2018), high affinity calcium indicators like Oregon Green BAPTA-1 (Emptage et al, 1999(Emptage et al, , 2003Ward et al, 2006;Enoki et al, 2009;Padamsey et al, 2017Padamsey et al, , 2019 or the glutamate sensor SF-iGluSnFR (Jensen et al, 2019;Soares et al, 2019). P(r) correlates with structural features of synapses such as the active zone area (Schikorski and Stevens, 1997;Holderith et al, 2012) and also with the readily releasable pool size (Dobrunz and Stevens, 1997) which is thought to consist of those vesicles docked at the active zone (Schikorski and Stevens, 1997;Murthy et al, 2001).…”

The fate of hippocampal synapses depends on the sequence of plasticity-inducing events

“…Failure to evoke postsynaptic CSBs upon oTFS led to presynaptic depression in our experiments, which was followed by increased spine elimination ( Figure 3F). This effect has been shown to be mediated by autocrine glutamate signaling at the presynaptic terminal and may not involve postsynaptic signaling (Padamsey, Tong and Emptage, 2017). If, on the other hand, the postsynaptic neuron is driven to spike, retrograde signaling via NO (nitric oxide) leads to an increase in release probability, which explains why we did not see presynaptic depression in synapses that experienced CSBs ( Figure 2C).…”