title: Differential Presynaptic ATP Supply for Basal and High-Demand Transmission.
abstract: The relative contributions of glycolysis and oxidative phosphorylation to neuronal presynaptic energy demands are unclear. In rat hippocampal neurons, ATP production by either glycolysis or oxidative phosphorylation alone sustained basal evoked synaptic transmission for up to 20 min. However, combined inhibition of both ATP sources abolished evoked transmission. Neither action potential propagation failure nor depressed Ca2+influx explained loss of evoked synaptic transmission. Rather, inhibition of ATP synthesis caused massive spontaneous vesicle exocytosis, followed by arrested endocytosis, accounting for the disappearance of evoked postsynaptic currents. In contrast to its weak effects on basal transmission, inhibition of oxidative phosphorylation alone depressed recovery from vesicle depletion. Local astrocytic lactate shuttling was not required. Instead, either ambient monocarboxylates or neuronal glycolysis was sufficient to supply requisite substrate. In summary, basal transmission can be sustained by glycolysis, but strong presynaptic demands are met preferentially by oxidative phosphorylation, which can be maintained by bulk but not local monocarboxylates or by neuronal glycolysis.SIGNIFICANCE STATEMENTNeuronal energy levels are critical for proper CNS function, but the relative roles for the two main sources of ATP production, glycolysis and oxidative phosphorylation, in fueling presynaptic function in unclear. Either glycolysis or oxidative phosphorylation can fuel low-frequency synaptic function and inhibiting both underlies loss of synaptic transmission via massive vesicle release and subsequent failure to endocytose lost vesicles. Oxidative phosphorylation, fueled by either glycolysis or endogenously released monocarboxylates, can fuel more metabolically demanding tasks such as vesicle recovery after depletion. Our work demonstrates the flexible nature of fueling presynaptic function to maintain synaptic function.
authors.affiliation: Department of Psychiatry.|Graduate Program in Neuroscience, and.
authors.forename: Courtney
authors.identifier: 0000-0002-4171-4216
authors.initials: C
authors.lastname: Sobieski
authors.affiliation: Department of Psychiatry.|Medical Scientist Training Program, Washington University School of Medicine, St. Louis, Missouri 63110.
authors.forename: Michael J
authors.identifier: 0000-0001-7663-2635
authors.initials: MJ
authors.lastname: Fitzpatrick
authors.affiliation: Department of Psychiatry, menneris@wustl.edu.|Department of Neuroscience.|Taylor Family Institute for Innovative Psychiatric Research.
authors.forename: Steven J
authors.identifier: 0000-0003-0868-0664
authors.initials: SJ
authors.lastname: Mennerick
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects; D002478:Cells, Cultured; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006019:Glycolysis / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018377:Neurotransmitter Agents / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010766:Phosphorylation / Q000187:drug effects; D011189:Potassium Chloride / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D055366:Synaptic Potentials / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology*; D013572:Synaptic Vesicles / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D018377:Neurotransmitter Agents; D011189:Potassium Chloride; D000255:Adenosine Triphosphate
keywords: astrocyte; glutamate; glycolysis; neuroenergetics; presynaptic