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Neuroenergetics and the kinetic design of excitatory synapses

Nature Reviews Neuroscience volume 6, pages 841–849 (2005)Cite this article

Key Points

  • The energy supply to the brain limits the timescale of the brain's information processing to the millisecond range.

  • The energy supply therefore imposes a low affinity on AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors, in order that their response is terminated in milliseconds when glutamate is removed from the synaptic cleft.

  • For diffusion to remove glutamate from the synaptic cleft in milliseconds, the diameter of synaptic boutons cannot be larger than ∼1 μm; therefore, the energy supply to the brain limits bouton size.

  • When glutamate is released at many nearby synapses, hindering clearance from the synaptic cleft by diffusion, in order for glutamate to be removed in milliseconds the initial rate of glutamate removal by transporters has evolved to occur in milliseconds; therefore, the energy supply to the brain sets the rate of this initial transporter step.

  • The high affinity of NMDA (N-methyl-D-aspartate) receptors is determined by their role as coincidence detectors on a timescale of tens of milliseconds, which requires NMDA receptor activation to last much longer than the AMPA receptor activation produced by a brief glutamate transient.

  • The ionic stoichiometry of glutamate transporters, with three Na+ ions being co-transported with each glutamate anion, is set by the need to reduce the extracellular glutamate concentration below the sub-micromolar value that will activate high-affinity NMDA receptors. Therefore, the stoichiometry is directly determined by the timescale on which NMDA receptors mediate coincidence detection.

Abstract

Why is the characteristic timescale of neural information processing in the millisecond range, corresponding to a 'clock speed' of about 1 kHz, whereas the clock speed of modern computers is about 3 GHz? Here we investigate how the brain's energy supply limits the maximum rate at which the brain can compute, and how the molecular components of excitatory synapses have evolved properties that are matched to the information processing they perform.

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Figure 1: Schematic diagram of a glutamatergic synapse.
Figure 2: Distribution of signalling energy expenditure.
Figure 3: Summary of kinetic properties of AMPA and NMDA receptors.
Figure 4: Kinetic properties of glutamate receptors.

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Acknowledgements

We are grateful to B. Barbour, M. Häusser, S. Laughlin and A. Silver for helpful discussion. Supported by the Wellcome Trust and a Wolfson-Royal Society award.

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Authors and Affiliations

  1. Department of Physiology University College London, Gower Street, London, WC1E 6BT, UK

    David Attwell

  2. Department of Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK

    Alasdair Gibb

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Correspondence to David Attwell.

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DATABASES

Entrez Gene

AMPA receptors

EAAT4

GLAST

GLT1

Kainate receptors

mGluR receptors

NMDA receptors

FURTHER INFORMATION

Attwell's homepage

Glossary

MEMBRANE TIME CONSTANT

The product of the capacitance and resistance of the cell membrane, which sets the timescale over which membrane currents change the voltage. A small time constant means that the membrane potential can change rapidly.

MEMBRANE RESISTANCE

The ratio of the voltage change produced across the cell membrane to the size of current injected into the cell: the resistance is set by the number and conductance of the ion channels in the cell membrane.

MEMBRANE CAPACITANCE

The cell membrane separates and stores electrical charge, thereby producing an electrical capacitance, which increases in proportion to membrane area.

VOLTAGE-UNIFORM CELL

A spatially compact cell with no voltage gradients along its cytoplasm, so that the voltage across the cell membrane is the same everywhere (by contrast, cells with long dendrites are often not voltage-uniform).

CELL RESTING POTENTIAL

The membrane potential at which there is no net flow of current across the cell membrane.

NERNST POTENTIAL

The potential at which there is no net movement of an ionic species across the cell membrane, because the free energy decrease resulting from the ion moving down its concentration gradient is balanced by the free energy increase needed to move the ionic charge through the membrane's electric field.

DISSOCIATION CONSTANT

The ratio of the unbinding rate constant (koff) to the binding rate constant (kon) when transmitter binds to a receptor.

AMPLITUDE-WEIGHTED DECAY TIME CONSTANT

For a multi-exponentially decaying synaptic current, this is Σ aiτi / Σ ai, where ai and τi are the amplitude and time constant of each exponential component. An exponential decay with a time constant of this value and an amplitude Σ ai has the same area (that is, charge transfer) as the multi-exponential decay from which it is derived.

EC50

The concentration of agonist that evokes a half-maximal response.

IC50

The concentration of antagonist that produces a half-maximal inhibition of a response.

Q10

The ratio of reaction rates for a 10°C increase in temperature.

SYMMORPHOSIS

According to this theory, animal design is optimized such that structure satisfies but does not exceed functional requirements.

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Attwell, D., Gibb, A. Neuroenergetics and the kinetic design of excitatory synapses. Nat Rev Neurosci 6, 841–849 (2005). https://doi.org/10.1038/nrn1784

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