Neuronal metabolic support

The brain produces energy by oxidizing glucose; the brain receives glucose and O2 from the blood supply. Glucose is transported across the blood-brain barrier via glucose transporter type 1 (GLUT1), which is specifically expressed in endothe-lial cells forming the capillary walls. Following transport across the blood-brain barrier, glucose is released into the extracellular space and is accumulated by neural cells via more plasmalemmal glucose transporters (Figure 7.12); neurones predominantly express GLUT3, whereas astrocytes possess GLUT1. Upon entering the cells, glucose is oxidized through glycolysis and the tricarboxylic acid cycle (TCA or Krebs cycle), which are central steps in energy production. Neurones account for about 90 per cent of brain energy consumption, and glial cells are

Presynaptic

Presynaptic

Glycolysis Lactate Astrocyte

Stimulation of GLUT1

Figure 7.12 The 'astrocyte-neuronal lactate shuttle': a mechanism by which astrocytes can provide an energy substrate to active neurones. The scheme shows biochemical and physiological pathways that have been demonstrated in astrocytes and neurones. These provide the substrate of the astroglial-neuronal lactate shuttle, detailed explanations of which are given in the text. Astrocytes take up glucose (via GLUT1) and convert it pyruvate and then lactate (via LDH5). Glutamate released during neuronal activity is taken up by astrocytes and triggers them to release lactate (via MCT-2), which is subsequently taken up by the neurone (via MCT-1), which utilizes it as a metabolic substrate (via LDH1). This provides a mechanism for coupling neuronal activity and astrocyte metabolism.

Abbreviations: GLUT1 - astroglial glucose transporter type 1; GLUT3 - neuronal glucose transporter type 3; LDH1 and LDH5 - lactate dehydrogenase type 1 and 5; MCT-1 and MCT-2 monocarboxylase transporters 1 and 2

Stimulation of GLUT1

Figure 7.12 The 'astrocyte-neuronal lactate shuttle': a mechanism by which astrocytes can provide an energy substrate to active neurones. The scheme shows biochemical and physiological pathways that have been demonstrated in astrocytes and neurones. These provide the substrate of the astroglial-neuronal lactate shuttle, detailed explanations of which are given in the text. Astrocytes take up glucose (via GLUT1) and convert it pyruvate and then lactate (via LDH5). Glutamate released during neuronal activity is taken up by astrocytes and triggers them to release lactate (via MCT-2), which is subsequently taken up by the neurone (via MCT-1), which utilizes it as a metabolic substrate (via LDH1). This provides a mechanism for coupling neuronal activity and astrocyte metabolism.

Abbreviations: GLUT1 - astroglial glucose transporter type 1; GLUT3 - neuronal glucose transporter type 3; LDH1 and LDH5 - lactate dehydrogenase type 1 and 5; MCT-1 and MCT-2 monocarboxylase transporters 1 and 2

responsible for the remaining 10 per cent; neurones require a continuous supply of energy to fuel their Na+-K+ ATPases (Na+-K+ pumps), which are constantly active to maintain ion gradients across neuronal cell membranes in the face of the continuous ionic fluxes during synaptic activity and action potential propagation. However, monitoring the distribution of glucose in the brain tissue has demonstrated that it is accumulated equally by neurones and astroglial cells. This implies the involvement of an intermediate product of glucose utilization, which is produced by astrocytes and subsequently transported to neurones. Furthermore, the utilization of glucose by the brain strongly depends on neural activity, a process that can be readily demonstrated by functional brain imaging, for example, positron emission tomography.

It turns out that astrocytes are ideally situated and have the biochemical machinery to provide metabolic support for neurones via the so-called

'astrocyte-neurone lactate shuttle'. Although it remains to be demonstrated that astrocytes provide metabolic support during normal neuronal activity in the mammalian brain, this has been shown in the honeybee retina and during metabolic stress in mammals.

Astroglial biochemical processing of glucose takes a specific route, known as aerobic glycolysis, by which glucose is converted into pyruvate and then into lactate in the presence of oxygen; the latter step is catalyzed by lactate dehydrogenase type 5 (LDH5) exclusively expressed in astrocytes. Aerobic glycolysis in astroglial cells is closely linked to their ability to accumulate and process glutamate. The major fraction of glutamate released during synaptic activity is accumulated by perisynaptic astrocytes via Na+-dependent glutamate transporters (see Chapters 5.7 and 7.8). Glutamate accumulation into the astrocyte leads to an increase in cytosolic Na+ concentration, which in turn activates the Na+ -K+ ATPase (Na+-K+ pumps), which expels the excess Na+ into the extracellular space. Activation of Na+-K+ ATPase stimulates phosphoglycerate kinase and triggers the process of aerobic glycolysis, which produces lactate. Lactate is then released into the extracellular space and finally taken up by neurones by two transporters, monocar-boxylase transporter 1 and 2 (MCT-1 and 2); MCT-2 is predominantly expressed by neurones, and MCT-1 by astrocytes. Once transported into the neurone, lactate is converted into pyruvate by lactate dehydrogenase type 1 (LDH1), which is expressed in neurones (as well as other lactate-consuming tissues). Pyruvate enters the TCA cycle and is utilized to produce energy.

Thus, glutamate released in the course of synaptic transmission acts as a specific signal on astrocytes to increase their delivery of an energy supply to active nerve cells. Every molecule of glutamate taken up by the astrocyte brings with it three Na+ ions. This activates Na+/K+ ATPase and aerobic glycolysis, which produces two molecules of ATP and two molecules of lactate from one molecule of glucose. The ATP so produced is consumed by Na+/K+ ATPase (one ATP molecule for expelling the three Na+ ions accumulated from glutamate transport), and by glutamine synthetase (one ATP molecule is needed for conversion of one molecule of the accumulated glutamate into one molecule of glutamine). The resulting two molecules of lactate are transported to the neurone, where each lactate molecule, being processed through the TCA cycle, delivers 17 molecules of ATP. This process of activity-induced 'astrocyte-neurone lactate shuttle' is further assisted by specific stimulation of astroglial glucose transporters by glutamate, which rapidly (in ~10 seconds) induces a two to three fold increase in astrocyte GLUTl-mediated glucose uptake.

Besides regulating the activity-dependent nourishment of neurones through the glucose-lactate shuttle, astrocytes also contain the brain reserve energy system. This system relies upon glycogen, which in the brain is present almost exclusively in astroglial cells. Glycogen is mobilized and turned into glucose upon intensive stimulation of the CNS. Subsequently, the glucose so-produced can be used by neurones (through the lactate shuttle), or by astrocytes themselves to meet high energy demands in response to intensive synaptic activity.

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