The five papers published by Hodgkin and Huxley in 1952 are seminal works in the field of physiology, earning their authors the Nobel Prize in 1963, and ushering in the era of membrane biophysics. The papers present a considerable challenge to the novice student, but this has been partly allayed by recent publications that have updated the reporting of current and voltage to reflect the modern convention, and two books that describe the contents of the papers in detail. A disadvantage is that these guides comprise hundreds of pages, requiring considerable time and energy on behalf of the reader. We present a concise guide to the Hodgkin and Huxley papers that includes only essential content, with the data presented in a linear and logical manner. We have color-coded figures for ease of understanding and included boxes that summarise key information for easy reference. It is our expectation that this Illuminations article will act an accessible introduction for students to the work of Hodgkin and Huxley, and hopefully foster an appreciation for a fascinating story that repays in depth study.

The application of physico-chemical principles has been routinely used to explain various physiological concepts. The Nernst equation is one example of this, used to predict the potential difference created by the trans-membrane ion gradient resulting from uneven ion distribution within cellular compartments and the interstitial space. This relationship remains of fundamental importance to the understanding of electrical signalling in the brain, which relies on current flow across cell membranes. We describe four distinct occasions where the Nernst equation was ingeniously applied in experimental design to illuminate diverse cellular functions, from the dependence of the action potential on Na+ influx, to K+ buffering in astrocytes. These examples are discussed with the aim of inspiring students to appreciate how the application of seemingly textbook bound concepts can dictate novel experimental design across physiological disciplines.

In the course of action potential firing, all axons and neurons release K+ from the intra- cellular compartment into the interstitial space to counteract the depolarizing effect of Na+ influx, which restores the resting membrane potential. This efflux of K+ from axons results in K+ accumulation in the interstitial space, causing depolarization of the K+ reversal potential (EK), which can prevent subsequent action potentials. To ensure optimal neuronal function, the K+ is buffered by astrocytes, an energy-dependent process, which acts as a sink for interstitial K+, absorbing it at regions of high concentration and distributing it through the syncytium for release in distant regions. Pathological processes in which energy production is compromised, such as anoxia, ischemia, epilepsy and spreading depression, can lead to excessive interstitial K+ accumulation, disrupting sensitive trans-membrane ion gradients and attenuating neuronal activity. The changes that occur in interstitial [K+] resulting from both physiological and pathological processes can be monitored accurately in real time using K+-sensitive microelectrodes, an invaluable tool in electrophysiological studies.

Action potential conduction in axons triggers trans‐membrane ion movements, where Na + enters and K + leaves axons, leading to disruptions in resting trans‐membrane ion gradients that must be restored for optimal axon conduction, an energy dependent process. The higher the stimulus frequency, the greater the ion movements and the resulting energy demand. In the mouse optic nerve (MON), the stimulus evoked compound action potential (CAP) displays a triple peaked profile, consistent with subpopulations of axons classified by size producing the distinct peaks. The three CAP peaks show differential sensitivity to high‐frequency firing, with the large axons, which contribute to the 1st peak, more resilient than the small axons, which produce the 3rd peak. Modeling studies predict frequency dependent intra‐axonal Na + accumulation at the nodes of Ranvier, sufficient to attenuate the triple peaked CAP. Short bursts of high‐frequency stimulus evoke transient elevations in interstitial K + ([K + ] o ), which peak at about 50 Hz. However, powerful astrocytic buffering limits the [K + ] o increase to levels insufficient to cause CAP attenuation. A post‐stimulus [K + ] o undershoot below baseline coincides with a transient increase in the amplitudes of all three CAP peaks. The volume specific scaling relating energy expenditure to increasing axon size dictates that large axons are more resilient to high‐frequency firing than small axons.

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