Action Potential Energy Efficiency Varies Among Neuron Types in Vertebrates and Invertebrates

Abstract

The initiation and propagation of action potentials (APs) places high demands on the energetic resources of neural tissue. Each AP forces ATP-driven ion pumps to work harder to restore the ionic concentration gradients, thus consuming more energy. Here, we ask whether the ionic currents underlying the AP can be predicted theoretically from the principle of minimum energy consumption. A long-held supposition that APs are energetically wasteful, based on theoretical analysis of the squid giant axon AP, has recently been overturned by studies that measured the currents contributing to the AP in several mammalian neurons. In the single compartment models studied here, AP energy consumption varies greatly among vertebrate and invertebrate neurons, with several mammalian neuron models using close to the capacitive minimum of energy needed. Strikingly, energy consumption can increase by more than ten-fold simply by changing the overlap of the Na⁺ and K⁺ currents during the AP without changing the APs shape. As a consequence, the height and width of the AP are poor predictors of energy consumption. In the Hodgkin–Huxley model of the squid axon, optimizing the kinetics or number of Na⁺ and K⁺ channels can whittle down the number of ATP molecules needed for each AP by a factor of four. In contrast to the squid AP, the temporal profile of the currents underlying APs of some mammalian neurons are nearly perfectly matched to the optimized properties of ionic conductances so as to minimize the ATP cost. Neurons produce a myriad of action potentials with different shapes and varying heights and widths; underlying these action potentials are highly nonlinear, voltage-dependent ionic conductances with varying biophysical properties. Each action potential comes at a cost: the brain uses a substantial portion of its total energy budget to generate and propagate action potentials. Recent results show that some mammalian action potentials have biophysical properties that make them energy efficient. Yet, how widespread are energy efficient action potentials? Using mathematical analysis and modeling, we show that there is no direct relationship between the height, width, and the energy consumption of a single action potential. Furthermore, we establish that many mammalian action potentials have biophysical properties that reduce the overlap between their inward and outward currents so as to minimize energy consumption. This reduction in overlap results from a combination of ion channel properties uniquely tailored for each particular neuron type and the functional purpose of the action potential in that neuron. By comparing the measured biophysical parameters to the parameters produced by numerical optimization for maximal energy-efficiency, we argue that natural selection for energy-efficiency could help explain both the shape of the action potential and the underlying biophysics of ionic currents.