FIGURE 2.

Neuron-Astrocyte metabolic interdependence. Representation of the metabolite flow between blood vessels, astrocytes and synaptic terminals of neurons. Glucose from the blood supply transverses the vessel endothelium and enveloping astrocyte endfeet via GLUT1. Glucose then enters aerobic glycolysis, with marginal contribution toward the TCA due to reduced PDH activity. Resulting pyruvate is almost exclusively transformed into lactate via the activity of LDH5. LDH5 is composed of LDHA subunits which preferentially drive the reaction toward consuming NADH and creating lactate, replenishing the NAD⁺ pool for increased glycolytic activity. Lactate is then exported via MCT1 and MCT4 and it is taken up by neurons via MCT2. In the neuron, lactate is metabolized back into pyruvate via LDH1. LDH1 is mainly composed of LDHB subunits which preferentially drive the reaction toward consuming NAD⁺ and creating pyruvate, replenishing the pool of available NADH. Pyruvate fuels the TCA cycle and OXPHOS, producing ATP necessary for replenishing pre-synaptic glutamate vesicles. Upon neuronal activation, glutamate is released into the synapse and binds to post-synaptic mGLUR GPCRs, ultimately resulting in a Ca²⁺ influx and signal propagation. Free glutamate in the synaptic cleft is re-uptaken by adjacent astrocytes via EAATs which co-transport Na⁺ and K⁺. Glutamate enters the glutamate-glutamine cycle and is metabolized into glutamine by GS. Glutamine is then exported and taken up by neurons, where it is turned back into glutamate by GLS and is used to replenish glutamate vesicles. Alternatively, glutamate is metabolized into α-KG that enters the TCA cycle and supplements ATP production. ATP is then used by Na⁺/K⁺ ATPases to re-establish the ionic gradient, replenishing the available ADP pool to stimulate glycolysis. Abbreviations: α-KG, α-ketoglutarate; ADP, adenosine diphosphate; ATP, adenosine triphosphate; EAAT, excitatory amino acid transporter; GCPR, G-protein-coupled receptor; Glc, glucose; Gln, glutamine; GLS, glutaminase; Glu, glutamate; GLUT, glucose transporter; GS, glutamate synthase; Lac, lactate; LDH, lactate dehydrogenase; MCT, monocarboxylate transporter; mGLUR, metabotropic glutamate receptor; NAD, nicotinamide adenine dinucleotide; NADH, nicotinamide adenine dinucleotide, reduced; OXPHOS, oxidative phosphorylation; PDH, pyruvate dehydrogenase; PKM1/M2, pyruvate kinase isozyme M1/M2; Pyr, pyruvate; TCA, tricarboxylic acid.