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

Author:

Padamsey Zahid12ORCID,Tong Rudi1,Emptage Nigel1ORCID

Affiliation:

1. Department of Pharmacology, University of Oxford, Oxford, United Kingdom

2. Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK

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.

Funder

Medical Research Council

Biotechnology and Biological Sciences Research Council

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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