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A generous helping of energy is needed to support the activity of the human brain. This glucose-guzzling organ makes up roughly 2% of the body's mass, but accounts for about 20% of the energy consumed at rest.

The brain's energy requirements have probably constrained its evolution, shaping the wiring patterns, signal encoding and synaptic properties of neurons. On page 841 of this issue, Attwell and Gibb consider how energy availability limits the maximum rate at which the brain can compute, and how the molecular components of excitatory synapses have evolved properties that reflect the information processing they perform in the face of high energy demands. Take AMPA receptors, which have evolved with low affinity so that their response is terminated in milliseconds when glutamate is removed from the synaptic cleft. Many other insights are provided by this refreshingly lucid account of the design principles behind excitatory synaptic transmission.

Mitochondria are responsible for satisfying the brain's hunger for energy, converting the latent energy of nutrient molecules into the stored energy of ATP. But, as Andrews, Diano and Horvath discuss on page 829, there are benefits to uncoupling the mitochondrial oxidation of energy substrates from the generation of a proton gradient that drives the phosphorylation of ADP to form ATP. The authors focus on the intriguing subject of neuronal uncoupling proteins. By regulating mitochondrial biogenesis, calcium flux, free radical production and local temperature, these proteins are proposed to have unique roles in neuroprotection and neuromodulation.

Research into neuronal uncoupling proteins is still in its infancy and many challenges lie ahead. An important goal will be to promote uncoupling pharmacologically without compromising the ability of cells to fuel the normal functions of the brain.

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In this issue. Nat Rev Neurosci 6, 819 (2005). https://doi.org/10.1038/nrn1803

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