The energetics of CNS white matter

Abstract

The energetics of CNS white matter are poorly understood. We derive a signaling energy budget for the white matter (based on data from the rodent optic nerve and corpus callosum) which can be compared with previous energy budgets for the gray matter regions of the brain, perform a cost-benefit analysis of the energetics of myelination, and assess mechanisms for energy production and glucose supply in myelinated axons. We show that white matter synapses consume ≤0.5% of the energy of gray matter synapses and that this, rather than more energy-efficient action potentials, is the main reason why CNS white matter uses less energy than gray matter. Surprisingly, while the energetic cost of building myelin could be repaid within months by the reduced ATP cost of neuronal action potentials, the energetic cost of maintaining the oligodendrocyte resting potential usually outweighs the saving on action potentials. Thus, although it dramatically speeds action potential propagation, myelination need not save energy. Finally, we show that mitochondria in optic nerve axons could sustain measured firing rates with a plausible density of glucose transporters in the nodal membrane, without the need for energy transfer from oligodendrocytes.

Figure 1.

Comparing gray and white matter energy consumption. A–C, Top (bar graphs), Calculated absolute energy use on different cellular processes in the cortex [A; adapted from Attwell and Laughlin (2001)], and the partially (B) and fully (C) myelinated optic nerve. Bottom (pie charts), Distribution of ATP usage on signaling and housekeeping processes in the cortex (A), and the partially (B) and fully (C) myelinated optic nerve. D, Theoretically estimated rates of glucose usage in gray and white matter regions. E, Experimentally estimated rates of glucose uptake [obtained from 2-deoxyglucose uptake (Sokoloff et al., 1977)] in gray and white matter regions (1 μmole/100 g/min equals 1.67 × 10⁻⁷ moles/kg/s).

Figure 2.

The energetic cost of making myelin and the ATP saved on axonal action potentials in the guinea pig optic nerve. A, The ATP cost, per length of internode, for assembling myelin from local lipid and protein resources increases quadratically with axon diameter (Eq. 2 of the Materials and Methods). Data points are labeled with the ganglion cell type(s) of each diameter [from the study by Perge et al. (2009)]. B, The ATP saving per action potential, per length of internode, conferred by myelin increases approximately linearly with axon diameter (dashed straight line has slope predicted from Eq. 3 of the Materials and Methods when C_L is set to zero). C, The number of action potentials required to pay back the cost of myelination increases approximately linearly with axon diameter (dashed straight line has slope predicted from Eq. 4 of the Materials and Methods when C_L is set to zero). D, Taking into account mean firing rates [inset: experimental data from which a linear axon diameter-firing rate relationship was derived in the study by Perge et al. (2009)], the time taken to pay back myelination decreases with axon diameter.

Figure 3.

The action potential firing rate needed for myelination to save energy in the long term. Open circles show, as a function of axon diameter, the critical firing rate above which myelination produces a larger saving of ATP on action potentials than is expended on the oligodendrocyte resting potential (from Eq. 8 of the Materials and Methods). Black squares show the measured mean firing rate for optic nerve axons of different classes (Perge et al., 2009).

Figure 4.

ATP supply and consumption in myelinated axons. A, ATP production by axonal mitochondria increases nonlinearly with axon diameter. B, ATP use on housekeeping, resting potentials, and action potentials all increase with axon diameter. ATP use on presynaptic processes was considered negligible. C, For axons larger than 0.9 μm in diameter, the ATP produced by axonal mitochondria can comfortably sustain the observed action potential firing rate, resting potential, and housekeeping processes. For smaller axons, there is up to a 38% deficit in the ATP available.

Figure 5.

Glucose supply to CNS internodes. A, B, The amount of glucose required by mitochondria in the internode (A), and therefore the number of glucose transporters required at the node (B) increases with axon diameter. C, Assuming a constant node length, the density of glucose transporters required in the nodal membrane increases with axon diameter, but remains below the density observed in other neurons [800/μm²: Li et al. (1994)].