Hodgkin and Huxley, two of the most famous neuroscientists, are impossible to avoid when discussing the mechanics of action potentials. In the words of the neurophysiologist Dr. Christof J. Schwiening,

Working together in 1939, and again from 1946 to 1952, Alan Hodgkin and Andrew Huxley formed one of the most productive and influential collaborations in the history of physiology. Their work…provided fundamental insights into nerve cell excitability. Their legacy is not only our understanding of how voltage-gated ion channels give rise to propagating action potentials, but also the very framework for studying and analysing ion channel kinetics. Their work won them a share of the 1963 Nobel Prize in Physiology or Medicine as well as laying the foundations for other Nobel Prize-winning work…

Ion channels are proteins that span the cellular membrane and allow ions (charged atoms like Calcium, Sodium, and Potassium) to move in and out of the cell freely. Image Credit: CyThera Pharmaceuticals

As Dr. Schwiening says in this quote, Hodgkin and Huxley are famous for discovering the mechanisms of action potentials through the study of giant squid axons. The oft-cited conclusion of their studies is that ion channels (small proteins inserted in the membrane of an axon) allow charged atoms to freely flow in and out of the cell when activated by a change in electrical potential. Ever since then, this concept has lain as an unquestioned foundation of all neuroscientific theories.

But, before the characterization of ion channels, Hodgkin and Huxley provided many possible explanations for the underlying cause of action potentials. In one of their initial theories, they described the observable depolarization of an action potential as a mere side effect of a physical change in membrane orientation. In other words, they suggested that an action potential could be a mechanical wave rather than an electrical wave.

There is a near perfect correlation between the potency of an anesthetic and its lipid solubility. Image Credit: Wikimedia Commons

Similarly, the Meyer-Overton hypothesis proposed that anesthetics assert their action by dissolving in the lipid membrane, changing its physical properties and raising the threshold necessary to create an action potential. This theory was supported by a linear correlation between the potency of an anesthetic and its solubility in lipids. But when ion channels were discovered the story shifted to proteins and any role of the membrane itself was quickly discounted.

Recently, there has been a resurgence in the idea that the lipid membrane plays an important role in cell signaling. It has been shown that synthetic lipid bilayers become permeable to polar molecules and ions near their phase transition temperature (i.e. around the temperatures where membranes start to melt or freeze), and this permeability is caused by the spontaneous creation of pores in the membrane. This strongly suggests that, given the right conditions, a biological membrane could admit the passage of ions without the need for protein ion channels.

A soliton moving through water in a narrow chamber. Solitons are waves that don’t lose amplitude as they travel, which is a well-established property of action potentials. Image Credit: Gyfcat

Fascinatingly, these kinds of phase transitions have been observed in the lipid bilayer of a neuron when action potentials occur. It has also been shown that a mechanical pulse accompanies the peak electrical activity of an action potential. With this evidence in mind, a new theory of action potential propagation has been proposed called The Soliton Model of Nerve Pulse Propagation. This theory applies thermodynamic principles to action potentials by describing and modeling them as traveling density pulses — sound waves that move through the lipid bilayer by forcing a localized packet of membrane to transition from a fluid-mosaic liquid state to a more ordered gel-like state.

This idea has some striking implications regarding the way our brains function. For example, the soliton model suggests that the Meyer-Overton hypothesis was correct — anesthetics exert their effects by stabilizing neuronal membranes which prevents the lipid bilayer from achieving a phase transition. This is very similar to the way in which table salt makes it more difficult for water to boil or freeze. A soliton model of action potential propagation could also support the established phenomenon of neural backpropagation — action potentials that move backwards — because solitons can pass through one another unimpeded.

Even if this model is false, the very idea can change the way we think about nervous system health by reminding us that the complexity of our brains is far too immense for scientific theories to perfectly encapsulate. As the old adage goes, “all models are wrong; some models are useful.” It might be time for scientists and physicians to take a hard look in the mirror and ask ourselves if the electrical model of action potential propagation has outlived its utility.