1. Neuron-Astrocyte Interactions: Partnership for Normal Function and Disease in the Central Nervous System 
Eduardo E. Benarroch, MD 
Mayo Clinic Proceedings 
Volume 80, Issue 10, Pages (October 2005)
DOI: /
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2. FIGURE 1
General interactions among neurons, astrocytes, and brain capillaries. The astrocytes are polarized into 2 domains, one facing the synapses and another forming the astrocytic end-foot processes that abut the capillaries. Astrocytes are connected extensively by gap junctions, forming a syncytiumlike organization, and may participate in paracrine interactions mediated by the release of mediators through connexin 43 hemichannels. There are reciprocal interactions between the astrocytes and the presynaptic and postsynaptic elements.
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3. FIGURE 2
Propagation of the excitatory glutamatergic signal via the astrocytic network. Glutamate released from excitatory synapses acts via metabotropic glutamate receptors (mGluR), resulting in production of inositol triphosphate (IP3), which triggers mobilization of Ca2+ from the endoplasmic reticulum (ER). This initiates Ca2+ waves that propagate to reach variable distances throughout the astrocytic syncytium. The propagation of Ca2+ signals involves release of adenosine triphosphate (ATP) from connexin 43 hemichannels. The ATP acts via P2Y-type receptors to activate IP3 production and Ca2+ release in the neighboring astrocytes. The Ca2+ signal triggers release of glutamate from the astrocyte, which appears to occur by exocytosis and to involve the effects of prostaglandin E2 (PgE2). Glutamate released from astrocytes provides a feedback mechanism that modulates synaptic transmission. In addition, activated astrocytes release nicotinamide adenine dinucleotide (NAD+) via hemichannels. NAD+ is converted into cyclic adenosine diphosphate (ADP)-ribose (cADPR) by action of an ectoenzyme (E) located in the astrocyte membrane. The cADPR is then transported into the astrocyte, where it activates ryanodine receptors in the ER, triggering release of Ca2+.
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4. FIGURE 3
The uptake of synaptic glutamate via excitatory amino acid transporters (EAATs) in the astrocyte is the major mechanism preventing accumulation of glutamate in the synaptic space. Glutamate is transported into the astrocyte together with Na+ and intracellular accumulation of Na+ activates the Na+,K+-adenosine triphosphatase (ATPase). This leads to an increase in the adenosine diphosphate (ADP)/adenosine triphosphate (ATP) ratio and activation of glycolysis in the astrocytes. Glucose is transported by the endothelial cells and astrocytic end-foot processes via the glucose transporter (GLUT) 1. In the astrocyte, glucose is used for synthesis of glycogen and glycolysis with production of lactic acid. Astrocytes transport lactic acid via the H+-coupled monocarboxylate transporter (MCT) 1. Lactate is taken up by neurons via MCT2 and is converted to pyruvate, thus serving as a fuel to support neuronal metabolism. In the astrocyte, glutamate serves both as a metabolic fuel and as precursor of glutamine and glutathione. Glutamine is synthesized from glutamate and ammonia (NH3) by action of the glutamine synthetase and is transported to the neurons, where it is transformed back to glutamate by action of the enzyme glutaminase.
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5. FIGURE 4
Astrocytes are critically involved in the regulation of brain pH and extracellular K+. The activity of the astrocytic carbonic anhydrase leads to the production of protons (H+) and bicarbonate (HCO3−). Extrusion of H+ results in an “alkaline shift” in astrocytes, which is mirrored by acidification of the extracellular space. Bicarbonate is removed by a Cl−/HCO3− exchanger or other transport mechanisms. Spatial K+ buffering depends on the high permeability of the astrocytes to K+, reflecting the presence of inward rectifying K+ channels (Kir), such as Kir4.1, and the transfer K+ via gap junctions through the glial network. Net K+ uptake is mediated primarily by the Na+,K+-ATPase and the Na+-K+-2Cl− cotransporter (NKCC). The functional coupling between K4.1 and aquaporin 4 (AQP4) at the astrocyte end-foot process is critical for efficient K+ clearance from extracellular space. The NKCC-mediated K+ and Cl− influx in the astrocyte leads to cell swelling, which triggers release of Cl−, taurine, or glutamate by the opening of a volume-stimulated osmolyte and anion channels (VOSAC). EAAT = excitatory amino acid transporter; mGluR = metabotropic glutamate receptor.
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