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

Citation

Lucas SJ, Michel C, Marra V, Smalley JL, Hennig MH, Graham B & Forsythe ID (2018) Glucose and lactate as metabolic constraints on presynaptic transmission at an excitatory synapse. Journal of Physiology, 596 (9), pp. 1699-1721. https://doi.org/10.1113/JP275107

Abstract
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 (MCTs). 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.

Keywords
excitatory postsynaptic current; synaptic transmission; cerebral metabolism; Calyx of Held

Journal
Journal of Physiology: Volume 596, Issue 9

• Lucas et al_ final submited version.pdf