The energetic brain – A review from students to students

Abstract

The past 20 years have resulted in unprecedented progress in understanding brain energy metabolism and its role in health and disease. In this review, which was initiated at the 14th International Society for Neurochemistry Advanced School, we address the basic concepts of brain energy metabolism and approach the question of why the brain has high energy expenditure. Our review illustrates that the vertebrate brain has a high need for energy because of the high number of neurons and the need to maintain a delicate interplay between energy metabolism, neurotransmission, and plasticity. Disturbances to the energetic balance, to mitochondria quality control or to glia–neuron metabolic interaction may lead to brain circuit malfunction or even severe disorders of the CNS. We cover neuronal energy consumption in neural transmission and basic (‘housekeeping’) cellular processes. Additionally, we describe the most common (glucose) and alternative sources of energy namely glutamate, lactate, ketone bodies, and medium chain fatty acids. We discuss the multifaceted role of non‐neuronal cells in the transport of energy substrates from circulation (pericytes and astrocytes) and in the supply (astrocytes and microglia) and usage of different energy fuels. Finally, we address pathological consequences of disrupted energy homeostasis in the CNS.

Metabolic compartmentalization between astroglia and neurons in physiological and pathophysiological conditions of the neurovascular unit

“…If this intercellular compartmentalization between neurons and astroglia operates in the resting and/or activated brain, the measured CMR glc would reflect mainly astroglial glucose utilization, since neurons utilize lactate derived from astroglia. This hypothetical model, termed the “astrocyte‐neuron lactate shuttle hypothesis (ANLSH)”, was originally proposed by Pellerin and Magistretti in 1994 based on data obtained using cultured cells and was supported by our findings but has remained controversial for more than a quarter of a century …”

“…Co‐transported Na + and glutamate increase the intracellular concentration of Na + ([Na + ] i ), leading to the activation of Na + ,K + ‐ATPase; this, in turn, accelerates ATP production in astroglia. Whether ATP production in astroglia is dependent on glycolysis or the mitochondrial oxidative metabolism of glucose continues to be a matter of long‐lasting debate . An in vitro experiment showed that glutamate stimulation does, indeed, increase glucose consumption and lactate production by astroglia (i.e., aerobic glycolysis) .…”

“…Irrespective of accumulating evidence supporting the ANLSH, the fate of lactate, if it is really produced by astroglia via a glutamate signal from activated neurons, has remained a matter of controversy for more than 25 years . The original ANLSH followed by numerous reports proposed that activated neurons consume lactate produced by astroglia .…”

“…This hypothetical model, termed the "astrocyte-neuron lactate shuttle hypothesis (ANLSH)", was originally proposed by Pellerin and Magistretti in 1994 based on data obtained using cultured cells 66 and was supported by our findings 67,68 but has remained controversial for more than a quarter of a century. 69,70 metabolism is inhibited, while neurons cannot. 72 Glucose uptake or utilization (phosphorylation by hexokinase [HK]) can be quantified using cultured astroglia and neurons in vitro and in vivo using modern molecular techniques, 73 while the quantitation of oxygen consumption is more difficult.…”

“…Whether ATP production in astroglia is dependent on glycolysis or the mitochondrial oxidative metabolism of glucose continues to be a matter of longlasting debate. 69,70,82,83 An in vitro experiment showed that glutamate stimulation does, indeed, increase glucose consumption and lactate production by astroglia (i.e., aerobic glycolysis). [66][67][68]74 The functional activation of in vivo brain also induces transient increases in lactate production locally in distinct lesions of an activated site where glucose utilization is eventually increased.…”