Oxidative Phosphorylation, Not Glycolysis, Powers Presynaptic and Postsynaptic Mechanisms Underlying Brain Information Processing

Abstract

Neural activity has been suggested to initially trigger ATP production by glycolysis, rather than oxidative phosphorylation, for three reasons: glycolytic enzymes are associated with ion pumps; neurons may increase their energy supply by activating glycolysis in astrocytes to generate lactate; and activity increases glucose uptake more than O 2 uptake. In rat hippocampal slices, neuronal activity rapidly decreased the levels of extracellular O 2 and intracellular NADH (reduced nicotinamide adenine dinucleotide), even with lactate dehydrogenase blocked to prevent lactate generation, or with only 20% superfused O 2 to mimic physiological O 2 levels. Pharmacological analysis revealed an energy budget in which 11% of O 2 use was on presynaptic action potentials, 17% was on presynaptic Ca 2ϩ entry and transmitter release, 46% was on postsynaptic glutamate receptors, and 26% was on postsynaptic action potentials, in approximate accord with theoretical brain energy budgets. Thus, the major mechanisms mediating brain information processing are all initially powered by oxidative phosphorylation, and an astrocyte-neuron lactate shuttle is not needed for this to occur.

Spreading Depolarization-Induced Adenosine Accumulation Reflects Metabolic Status In Vitro and In Vivo

“…23,27,28 We compared our observations of adenosine accumulation with O 2 utilization and the oxidative transient of NAD(P)H during SD, across the range of different baseline conditions established in Figure 1.…”

The Oxygen Paradox of Neurovascular Coupling

“…1,2 The oxygen-glucose index of the brain is close to six in the resting state, 3,4 thus the brain consumes, on average, six molecules of oxygen per molecule glucose. The high-energy demand generates the need for a large amount of oxygen delivered via the blood stream.…”

“…An intuitive consequence of the facts mentioned above is the hypothesis that a feedback mechanism exists, which senses the tissue pO 2 and consequently transmits a signal to the vasculature such that CBF is adjusted to maintain a constant pO 2 . Evidence for such a mechanism has been found in brain slice experiments demonstrating a switch from vasoconstrictory to vasodilatory signaling of astrocytes when lowering oxygen concentration in the slices.…”

“…Evidence accumulates that dysfunction of the neurovascular unit has a role in Alzheimer's disease and stroke/small vessel disease and impairment of neurovascular coupling may be part of this dysfunction. 80,81,87,88 It can be speculated that impaired neurovascular coupling could lead to repeated drops in tissue pO 2 upon neuronal activation with initial short-term preservation of normal neuronal function but induction of inflammatory pathways that ultimately lead to long-term tissue damage. 80 However, no disease affects neurovascular coupling specifically while leaving baseline CBF, capillary morphology, endothelial function, etc.…”

“…Later, it has been pointed out by Buxton and Frank 75 that the large CBF increase may in fact be necessary for a small CMRO 2 increase because of the physical properties of the brain tissue (oxygen limitation model, see above). Following this argument, physiologic neurovascular coupling including a capillary pO 2 increase during activation could be termed 'tight' and in this sense, the positive BOLD signal that forms the basis of functional imaging as well as the negative BOLD signal observed during stimulus evoked reductions of neuronal activity, 90,91 e.g. ipsilaterally to somatosensory stimulation or in 'surround' regions of focal activation, could also represent 'tight coupling' of CBF and CMRO 2 .…”