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Glucose and lactate as metabolic constraints on presynaptic transmission at an excitatory synapse

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journal contribution
posted on 19.02.2018, 16:26 by Sarah J. Lucas, Christophe B. Michel, Vincenzo Marra, Joshua L. Smalley, Matthias H. Hennig, Bruce P. Graham, Ian D. Forsythe
The synapse has high energy demands, which increase during intense activity. Presynaptic ATP production depends on substrate availability and usage will increase during activity, which in turn could influence transmitter release and information transmission. We investigated transmitter release at the mouse calyx of Held synapse using glucose or lactate (10, 1 or 0 mm) as the extracellular substrates while inducing metabolic stress. High frequency stimulation (HFS) and recovery paradigms evoked trains of EPSCs monitored under voltage-clamp. Whilst postsynaptic intracellular ATP was stabilised by diffusion from the patch pipette, depletion of glucose increased EPSC depression during HFS and impaired subsequent recovery. Computational modelling of these data demonstrated a reduction in the number of functional release sites and slowed vesicle pool replenishment during metabolic stress, with little change in release probability. Directly depleting presynaptic terminal ATP impaired transmitter release in an analogous manner to glucose depletion. In the absence of glucose, presynaptic terminal metabolism could utilise lactate from the aCSF and this was blocked by inhibition of monocarboxylate transporters (MCT). MCT inhibitors significantly suppressed transmission in low glucose, implying that lactate is a presynaptic substrate. Additionally, block of glycogenolysis accelerated synaptic transmission failure in the absence of extracellular glucose, consistent with supplemental supply of lactate by local astrocytes. We conclude that both glucose and lactate support presynaptic metabolism and that limited availability, exacerbated by high intensity firing, constrains presynaptic ATP, impeding transmission through a reduction in functional presynaptic release sites as vesicle recycling slows when ATP levels are low.

Funding

This research was supported by the Biotechnology and Biological Sciences Research Council (IDF, MHH, BPG) and the Wellcome Trust (VM)

History

Citation

The Journal of Physiology, 2018

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/Biological Sciences/Neuroscience, Psychology and Behaviour

Version

AM (Accepted Manuscript)

Published in

The Journal of Physiology

Publisher

Wiley, Physiological Society

issn

0022-3751

eissn

1469-7793

Acceptance date

02/02/2018

Copyright date

2018

Available date

12/02/2019

Publisher version

http://onlinelibrary.wiley.com/doi/10.1113/JP275107/abstract

Notes

The file associated with this record is under embargo until 12 months after publication, in accordance with the publisher's self-archiving policy. The full text may be available through the publisher links provided above.

Language

en

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