Lactate Transport via Glial MCT1 and Neuronal MCT2 Is Not Required for Synchronized Synaptic Transmission in Hippocampal Slices Supplied With Glucose

The metabolite lactate (L-lactate) has been hypothesized to represent an important energy source during brain activation. The contribution of lactate in fueling synchronized synaptic transmission during fast neural network oscillations underlying complex cortex function such as visual perception, memory formation, and motor activity is less clear, however. We explored the role of cellular lactate production and lactate transport (uptake and release) via the monocarboxylate transporters 1 and 2 (glial MCT1 and neuronal MCT2) during persistent gamma oscillations (frequency at around 40 Hz) and recurrent rhythmic events called sharp wave-ripples (with "ripples" at around 250 Hz) in cultured rat and acute mouse hippocampal slices (ex vivo) that received energy substrate supply with glucose (D-glucose) only. In addition, we assessed neuronal lactate dynamics during spontaneous activity ("resting state") and during electrical stimulation (10 Hz) in mouse primary neuron-astrocyte cultures (in vitro) receiving glucose only. We combined electrophysiology (local field potential recordings), tissue lactate analysis [ultra-performance liquid chromatography-mass spectrometry (UPLC-MS)], and live-cell fluorescence imaging [Förster resonance energy transfer (FRET) sensor Laconic]. We report that (1) lactate is produced during gamma oscillations when glucose is supplied and oxygen availability is unlimited (high oxygenation) for mitochondrial respiration. (2) The properties of gamma oscillations remain regular in the presence of the MCT1/2 blocker AR-C155858. (3) By contrast, MCT1/2 blockade fully suppresses gamma oscillations when mainly lactate is supplied. (4) The properties of sharp wave-ripples remain regular during MCT1/2 inhibition. (5) Lactate is produced in primary hippocampal neurons during spontaneous activity and electric stimulus-induced excitation, and it accumulates in the neuronal cytosol during MCT1/2 inhibition. In conclusion, lactate is produced in cortical tissue, including neurons fueled by glucose only. Moreover, lactate transport and lactate exchange ("shuttling") via glial MCT1 and neuronal MCT2 are not required to sustain synchronized synaptic transmission during fast neural network oscillations.

aerobic glycolysis; brain energy metabolism; lactate oxidation; monocarboxylate transporter; neurotransmission; tissue oxygenation.