title: A neuronal lactate uptake inhibitor slows recovery of extracellular ion concentration changes in the hippocampal CA3 region by affecting energy metabolism.
abstract: Astrocyte-derived lactate supports pathologically enhanced neuronal metabolism, but its role under physiological conditions is still a matter of debate. Here, we determined the contribution of astrocytic neuronal lactate shuttle for maintenance of ion homeostasis and energy metabolism. We tested for the effects of α-cyano-4-hydroxycinnamic acid (4-CIN), which could interfere with energy metabolism by blocking monocarboxylate-transporter 2 (MCT2)-mediated neuronal lactate uptake, on evoked potentials, stimulus-induced changes in K+, Na+, Ca2+, and oxygen concentrations as well as on changes in flavin adenine dinucleotide (FAD) autofluorescence in the hippocampal area CA3. MCT2 blockade by 4-CIN reduced synaptically evoked but not antidromic population spikes. This effect was dependent on the activation of KATPchannels indicating reduced neuronal ATP synthesis. By contrast, lactate receptor activation by 3,5-dihydroxybenzoic acid (3,5-DHBA) resulted in increased antidromic and orthodromic population spikes suggesting that 4-CIN effects are not mediated by lactate accumulation and subsequent activation of lactate receptors. Recovery kinetics of all ion transients were prolonged and baseline K+concentration became elevated by blockade of lactate uptake. Lactate contributed to oxidative metabolism as both baseline respiration and stimulus-induced changes in Po2were decreased, while FAD fluorescence increased likely due to a reduced conversion of FAD into FADH2These data suggest that lactate shuttle contributes to regulation of ion homeostatsis and synaptic signaling even in the presence of ample glucose.
authors: Neuroscience Research Center, Charité Universitätsmedizin, Berlin, Germany.
authors: Eskedar Ayele
authors: EA
authors: Angamo
authors: Neuroscience Research Center, Charité Universitätsmedizin, Berlin, Germany.
authors: Joerg
authors: J
authors: Rösner
authors: Department of Anesthesiology and Intensive Care, Charité Universitätsmedizin, Berlin, Germany.
authors: Agustin
authors: A
authors: Liotta
authors: Institute for Neurophysiology, Charité Universitätsmedizin, Berlin, Germany; and.
authors: Richard
authors: R
authors: Kovács
authors: Neuroscience Research Center, Charité Universitätsmedizin, Berlin, Germany; richard.kovacs@charite.de.
authors: Uwe
authors: U
authors: Heinemann
mesh_terms: D000818:Animals; D056654:CA3 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism*; D003373:Coumaric Acids / Q000494:pharmacology; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology*; D045604:Extracellular Fluid / Q000187:drug effects / Q000502:physiology*; D062385:Hydroxybenzoates / Q000494:pharmacology; D019344:Lactic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009924:Organ Culture Techniques; D051381:Rats; D017208:Rats, Wistar; D012118:Resorcinols / Q000494:pharmacology
chemical_list: D003373:Coumaric Acids; D062385:Hydroxybenzoates; D012118:Resorcinols; C007175:alpha-cyano-4-hydroxycinnamate; C076950:alpha-resorcylic acid; D019344:Lactic Acid
keywords: 4-CIN; FAD autofluorescence; extracellular potassium; lactate shuttle; monocarboxylate transporter; sodium and calcium concentrations