Neuroscience for Pre-Clinical Students

Neuron and astrocyte metabolism

Learning Objectives

• Describe the metabolic pathway of glucose and its metabolites and how they are utilized in the brain, and list the major energy-consuming processes in the brain.
• Describe the role of glial cells in neuron metabolism.
• Evaluate the interaction between astrocytes and neurons in the regulation of cerebral blood flow.
• Compare the metabolic profile of neurons and astrocytes.
• Review basic metabolic pathways, including: glycolysis, glycogen synthesis/olysis, transaminations, and glutathione synthesis.

The adult brain consumes about 25 percent of the glucose-derived energy and 20 percent of oxygen is dedicated to cerebral functions. The primary fuel to support the high energy demands of this tissue is supplied in the form of glucose, however, not all neuronal tissues oxidize glucose to the same extent. This section will address the distinct metabolic differences between astrocyte and neuronal metabolic profiles and how this interplay is essential for brain metabolic homeostasis.

As a brief review, glucose is taken up by the brain in an insulin-independent manner. The brain oxidizes glucose under most conditions with the exception of starvation states. Once the glucose is phosphorylated to glucose 6-phosphate (by hexokinase), it has three potential fates.

1. Glycolysis (either leading to lactate production or mitochondrial metabolism),
2. Pentose phosphate pathway (PPP), or
3. Glycogen synthesis (only in astrocytes).

Neuron metabolism

To support the high energy demands imposed on neurons, they sustain a high rate of oxidative metabolism for ATP production compared to astrocytes. Despite this high rate of mitochondrial metabolism, glucose uptake is reduced when compared to astrocytes, in part due to the use of lactate as an energy source. Neurons show a preference for lactate over glucose when both substrates are present. There are several reasons why sustaining a low glycolytic rate but high oxidative rate is preferred in this tissue:

1. The bifunctional enzyme phosphofructokinase 2 (PFK2) is virtually absent in neurons, due to its constant proteasomal degradation. This enzyme is responsible for the generation of fructose 2,6-bisphosphate, which is an allosteric activator of the glycolytic enzyme phosphofructokinase 1 (PFK1).
2. Elevated glycolytic flux impairs metabolism through the PPP. Neurons purposefully reduce glycolytic flux to maintain metabolism through the PPP—which is essential for the production of NADPH through the reaction catalyzed by glucose 6-phosphate dehydrogenase.

To accommodate these two processes, neurons preferentially utilize lactate, which can be readily converted to pyruvate and enter the mitochondria. The lactate required for neuronal metabolism is produced by astrocytic glucose oxidation and is discussed below.