Ephaptic coupling

The early work performed by Katz and Schmitt demonstrated that ephaptic coupling between the two adjacent nerves was insufficient to stimulate an action potential in the resting nerve. Under ideal conditions the maximum depolarization observed was approximately 20% of the threshold stimulus.[4] However, conditions can be manipulated in such a way that the action potential from one neuron can be spread to a neighboring neuron. This was accomplished in one study in two experimental conditions: increased calcium concentrations, which lowered the threshold potential, or by submerging the axons in mineral oil, which increased resistance. While these manipulations do not reflect normal conditions, they do highlight the mechanisms behind ephaptic excitation.[7]

Ephaptic coupling has also been found to play an important role in inhibition of neighboring neurons. Depending on the location and identity of the neurons, various mechanisms have been found to underlie ephaptic inhibition. In one study, newly excited neighboring neurons interfered with already sustained currents, thus lowering the extracellular potential and depolarizing the neuron in relation to its surrounding environment, effectively inhibiting the action potential's propagation.[8]

Three-dimensional (3D) organization of the human neocortex.

Studies of ephaptic coupling have also focused on its role in the synchronization and timing of action potentials in neurons. In the simpler case of adjacent fibers that experience simultaneous stimulation the impulse is slowed because both fibers are limited to exchange ions solely with the interstitial fluid (increasing the resistance of the nerve). Slightly offset impulses (conduction velocities differing by less than 10%) are able to exchange ions constructively and the action potentials propagate slightly out of phase at the same velocity.

More recent research, however, has focused on the more general case of electric fields that affect a variety of neurons. It has been observed that local field potentials in cortical neurons can serve to synchronize neuronal activity.[9] Although the mechanism is unknown, it is hypothesized that neurons are ephaptically coupled to the frequencies of the local field potential. This coupling may effectively synchronize neurons into periods of enhanced excitability (or depression) and allow for specific patterns of action potential timing (often referred to as spike timing). This effect has been demonstrated and modeled in a variety of cases.[10][11]

A hypothesis or explanation behind the mechanism is "one-way", "master-slave", or "unidirectional synchronization" effect as mathematical and fundamental property of non-linear dynamic systems (oscillators like neurons) to synchronize under certain criteria. Such phenomenon was proposed and predicted to be possible between two HR neurons, since 2010 in simulations and modeling work by Hrg.[12] It was also shown that such unidirectional synchronization or copy/paste transfer of neural dynamics from master to slave neurons, could be exhibited in different ways. Hence the phenomenon is of not only fundamental interest but also applied one from treating epilepsy to novel learning systems. A study in July 2023 found that mathematical models of ephaptic coupling predicted in vivo data of neural activity.[13] The authors likened the electric field to a conductor of an orchestra and neurons to the musicians. Then the field,like the conductor, listens to the music and guides the musicians accordingly. In an opinion paper, they also suggested that not only neurons but other parts of the cytoskeleton generate electromagnetic fields that influence individual neurons, and called this cytoelectric coupling.[14] Synchronization of neurons is in principle unwanted behavior, as brain would have zero information or be simply a bulb if all neurons would synchronize. Hence it is a hypothesis that neurobiology and evolution of brain coped with ways of preventing such synchronous behavior on large scale, using it rather in other special cases.

Schematic representation of the bioelectromagnetic field distribution in the neocortex and gliocortex.

Schematic representation of neurons (N) and astrocytes (A) in layer 2–3 of the human neocortex.

As models of brain function using only neuronal and gap junction connections fail to explain its complexity ephaptic coupling is being added more to the equation to try and explain the isopotentiality of cortical astrocytes to maintain the bioelectromagnetic crosstalk between neurons and astrocytes in the neocortex.[15]

Different finite element geometries and meshes for muscle intercalated discs.

The electrical conduction system of the heart has been robustly established. However, newer research has been challenging some of the previously accepted models. The role of ephaptic coupling in cardiac cells is becoming more apparent. One author even goes so far as to say, “While previously viewed as a possible alternative to electrotonic coupling, ephaptic coupling has since come to be viewed as operating in tandem with gap junctions, helping sustain conduction when gap junctional coupling is compromised.”[16] Ephaptic interactions among cardiac cells help fill in the gaps that electrical synapses alone cannot account for. The proximity of sodium channels to gap junction plaques has been shown to relate to their effectiveness in driving ephaptic coupling action potential transmission.[17] There are also a number of mathematical models that now incorporate ephaptic coupling into predictions about electrical conductance in the heart.[18] Experimental work suggests that sodium channel-rich nanodomains located at sites of close contact between cardiac myocytes may constitute functional units of ephaptic coupling and selective disruption of these nanodomains resulted in arrhythmogenic conduction slowing, suggesting an important role for ephaptic coupling in the heart.[19] Potential ephaptic connections are now being considered in heart therapeutics.[20][21]

Epileptic seizures occur when there is synchrony of electrical waves in the brain. Knowing the role that ephaptic coupling plays in maintaining synchrony in electrical signals, it makes sense to look for ephaptic mechanisms in this type of pathology. One study suggested that cortical cells represent an ideal place to observe ephaptic coupling due to the tight packing of axons, which allows for interactions between their electrical fields. They tested the effects of changing extracellular space (which affects local electrical fields) and found that one can block epileptic synchronization independent of chemical synapse manipulation simply by increasing the space between cells.[22] Later, a model was created to predict this phenomenon and showed scenarios with greater extracellular spacing that effectively blocked epileptic synchronization in the brain.[23]

Neurons in the olfactory system are unmyelinated and densely packed and thus the often small effects of ephaptic coupling are more easily seen. A number of studies have shown how inhibition among neurons in the olfactory system work to fine-tune integration of signals in response to odor. This inhibition has been shown to occur from changes in electrical potentials alone.[8] The addition of ephaptic coupling to olfactory neuron models adds further support to the "dedicated-line" model in which each olfactory receptor sends its signal to one neuron. The inhibition due to ephaptic coupling would help account for the integration of signals that gives rise to more nuanced perception of smells.[24]

Synapses are typically formed where two neurons come in very close proximity. Ephaptic coupling may therefore arise across the synaptic cleft. Prominent examples are the fish Mauthner cell,[25] the chick ciliary ganglion,[26] the mammalian cerebellar basket synapse,[27] and the mammalian, developing calyx of Held synapse.[28]

In 1978, basic tests were being conducted on squid giant axons in order to find evidence of ephaptic events. It was shown that an action potential of one axon could be propagated to a neighboring axon. The level of transmission varied, from subthreshold changes to initiation of an action potential in a neighboring cell, but in all cases, it was apparent that there are implications of ephaptic coupling that are of physiological importance.[7]

One study tested the effects of ephaptic coupling by using both neurotransmitter antagonists to block chemical synapses and gap junction blockers to block electrical synapses. It was found that rhythmic electrical discharge associated with fetal neurons in the rat spinal cord and medulla was still sustained. This suggests that connections between the neurons still exist and work to spread signals even without traditional synapses. These findings support a model in which ephaptic coupling works alongside canonical synapses to propagate signals across neuronal networks.[32]

One of the few known cases of a functional system in which ephaptic coupling is responsible for an observable physiological event is in the Purkinje cells of the rat cerebellum.[27] It was demonstrated in this study that the basket cells which encapsulate some regions of Purkinje fibers can cause inhibitory effects on the Purkinje cells. The firing of these basket cells, which occurs more rapidly than in the Purkinje cells, draws current across the Purkinje cell and generates a passive hyperpolarizing potential which inhibits the activity of the Purkinje cell. Although the exact functional role of this inhibition is still unclear, it may well have a synchronizing effect in the Purkinje cells as the ephaptic effect will limit the firing time.

A similar ephaptic effect has been studied in the Mauthner cells of teleosts.[33]