Multifunctional role of astrocytes as gatekeepers of neuronal energy supply

Abstract

Dynamic adjustments to neuronal energy supply in response to synaptic activity are critical for neuronal function. Glial cells known as astrocytes have processes that ensheath most central synapses and express G-protein-coupled neurotransmitter receptors and transporters that respond to neuronal activity. Astrocytes also release substrates for neuronal oxidative phosphorylation and have processes that terminate on the surface of brain arterioles and can influence vascular smooth muscle tone and local blood flow. Membrane receptor or transporter-mediated effects of glutamate represent a convergence point of astrocyte influence on neuronal bioenergetics. Astrocytic glutamate uptake drives glycolysis and subsequent shuttling of lactate from astrocytes to neurons for oxidative metabolism. Astrocytes also convert synaptically reclaimed glutamate to glutamine, which is returned to neurons for glutamate salvage or oxidation. Finally, astrocytes store brain energy currency in the form of glycogen, which can be mobilized to produce lactate for neuronal oxidative phosphorylation in response to glutamatergic neurotransmission. These mechanisms couple synaptically driven astrocytic responses to glutamate with release of energy substrates back to neurons to match demand with supply. In addition, astrocytes directly influence the tone of penetrating brain arterioles in response to glutamatergic neurotransmission, coordinating dynamic regulation of local blood flow. We will describe the role of astrocytes in neurometabolic and neurovascular coupling in detail and discuss, in turn, how astrocyte dysfunction may contribute to neuronal bioenergetic deficit and neurodegeneration. Understanding the role of astrocytes as a hub for neurometabolic and neurovascular coupling mechanisms is a critical underpinning for therapeutic development in a broad range of neurodegenerative disorders characterized by chronic generalized brain ischemia and brain microvascular dysfunction.

Keywords: Alzheimer's disease; astrocytes; brain oxidative metabolism; epilepsy; glutamate-glutamine shuttle; ischemia; neurovascular coupling.

Figure 1

The glutamate-glutamine cycle. Glutamate (Glu) from pre-synaptic neurons stimulates post-synaptic neurons, and the signal is terminated by uptake of Glu from the synaptic cleft into astrocytes. Glu is primarily transported into astrocytes through Na⁺-dependent excitatory amino acid transporters, EAATs. This disrupts the astrocyte Na⁺ gradient and energy is consumed by the Na⁺/K⁺ ATPase to restore ionic concentrations. Glu is converted to: (a) glutamine (Gln) via glutamine synthase (GS) or (b) alpha-ketoglutarate (α-KG) by glutamate dehydrogenase (GDH) or aspartate aminotransferase (AAT) for subsequent oxidative metabolism in the TCA cycle. Gln is shuttled to neurons for glutamate production by phosphate-activated glutaminase (PAG) and the resulting Glu is repackaged in vesicles for further synaptic release.

Figure 2

The Astrocyte to Neuron Lactate Shuttle Hypothesis. Free glucose is taken up by astrocytes through GLUT1 transporters and converted to glucose-6-phosphate (Glc-6-P). Glc-6-P is stored as glycogen synthesized by glycogen synthase (GlyS). During greater energy demand, glycogenolysis, mediated by glycogen phosphorylase (GlyP), creates Glc-6-P for glycolysis. Synaptic transmission induces astrocyte glycolysis and lactate production through glutamate uptake. This increases glucose consumption and/or glycogen breakdown in astrocytes. Astrocyte lactate is transported into the extracellular space by MCT1 and taken up through MCT2 by neurons. Neurons can convert lactate (Lac) to pyruvate (Pyr) for oxidative phosphorylation.

Figure 3

Astrocyte intracellular Ca²⁺ elevations trigger release of vasoactive molecules. (1) PLA₂ is activated by Ca²⁺ and converts phospholipids (PL) to AA. AA is metabolized in astrocyte endfeet to PGE₂ (by COX) or EET [by cytochrome P450 epoxygenase (epoxy)] which dilate arterioles, or AA can diffuse to smooth muscle where ω-hydroxylase (ω-HY) converts it to 20-HETE and causes constriction. (2) K⁺ is released from astrocyte endfeet through BK_Ca, and the amount of K⁺ released is directly proportional to astrocyte Ca²⁺ level. K⁺ is taken up into smooth muscle through K_ir and causes dilation at low concentrations and constriction at high concentrations. (3) HO is activated by Ca²⁺ and produces CO, which diffuses to smooth muscle and triggers dilation.