RESUMEN
Metabolically, the brain is a highly active organ that relies almost exclusively on glucose as its energy source. According to the astrocyte-to-neuron lactate shuttle hypothesis, glucose is taken up by astrocytes and converted to lactate, which is then oxidized by neurons. Here we show, using two-photon imaging of a near-infrared 2-deoxyglucose analogue (2DG-IR), that glucose is taken up preferentially by neurons in awake behaving mice. Anaesthesia suppressed neuronal 2DG-IR uptake and sensory stimulation was associated with a sharp increase in neuronal, but not astrocytic, 2DG-IR uptake. Moreover, hexokinase, which catalyses the first enzymatic steps in glycolysis, was highly enriched in neurons compared with astrocytes, in mouse as well as in human cortex. These observations suggest that brain activity and neuronal glucose metabolism are directly linked, and identify the neuron as the principal locus of glucose uptake as visualized by functional brain imaging.
Asunto(s)
Astrocitos/metabolismo , Corteza Cerebral/metabolismo , Glucosa/metabolismo , Neuronas/metabolismo , ARN Mensajero/metabolismo , Vigilia , Anestésicos Disociativos/farmacología , Animales , Antimetabolitos , Astrocitos/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Células Cultivadas , Corteza Cerebral/efectos de los fármacos , Desoxiglucosa , Neuroimagen Funcional/métodos , Hexoquinasa/genética , Hexoquinasa/metabolismo , Humanos , Hipnóticos y Sedantes/farmacología , Inmunohistoquímica , Ketamina/farmacología , Ratones , Neuronas/efectos de los fármacos , Estimulación Física , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Espectroscopía Infrarroja Corta , Xilazina/farmacologíaRESUMEN
Astrocytes in hippocampal slices can dynamically regulate synaptic transmission in a process mediated by increases in intracellular Ca(2+). However, it is debated whether astrocytic Ca(2+) signals result in release of glutamate. We here compared astrocytic Ca(2+) signaling triggered by agonist exposure versus photolysis side by side. Using transgenic mice in which astrocytes selectively express the MrgA1 receptor, we found that receptor-mediated astrocytic Ca(2+) signaling consistently triggered neuronal hyperpolarization and decreased the frequency of miniature excitatory postsynaptic currents (EPSCs). In contrast, photolysis of caged Ca(2+) (o-nitrophenyl-EGTA) in astrocytes led to neuronal depolarization and increased the frequency of mEPSCs through a metabotropic glutamate receptor-mediated pathway. Analysis of transgenic mice in which astrocytic vesicular release is suppressed (dominant-negative SNARE mice) and pharmacological manipulations suggested that glutamate is primarily released by opening of anion channels rather than exocytosis. Combined, these studies show that photolysis but not by agonists induced astrocytic Ca(2+) signaling triggers glutamate release.
