Difference between revisions of "Draft:Two Forms of Electrical Transmission Between Neurons"

It has been argued that the function of the nervous system is to support movement and that it evolved because of its usefulness to organisms in navigating their environment (Llinás, 2001). Early observations established that nerves were required for muscle contraction. However, the mechanism underlying this interaction was unknown. An old, predominant, idea embraced by Rene Descartes was that muscle contraction resulted from the action of “animal spirits” running through hollow nerves (Piccolino, 1998; Finger, 2005). This and other speculative ideas were later disproved, leading to the consideration of alternative mechanisms. One of them was electricity (Franklin, 1751). The use of electricity for therapeutic purposes was popular in the second part of the 18th century, and electricity was capable of eliciting muscle contraction. In addition, because of its high travel velocity, electricity was ideally suited to be the agent responsible for nerve action, as some hypothesized (Finger, 2005). Furthermore, experimental evidence showed that certain fish were capable of generating electricity. All this preceding work and speculations paved the way to the studies conducted by Galvani (1791) which demonstrated that nerves and muscles generate electricity (“bioelectricity”) and, therefore, that electricity was the mysterious fluid or “animal spirit” responsible for nerve conduction and muscle contraction (Piccolino, 1998; Finger, 2005). We know now that these electrical currents result from the movement of charged ions across the cellular membrane following their electrochemical gradient (Hodgkin and Huxley, 1952; Armstrong, 2007). Galvani’s seminal studies led to the foundation of electrophysiology and to the discovery that brain function and, hence, animal behavior, depends upon electrophysiological computations, the only operational mode fast enough to support the required time frame of decision making by neural circuits. In other words, as emphasized by Llinás, electricity makes us who we are (Sohn, 2003).  

The question of whether transmission between neurons is mediated electrically or chemically ​(Figure1A) was posed formally in the 1870s, when the prevailing view of the nervous system was that it was a syncytium of connected nodes within a reticular structure. As stated by Eccles (Eccles, 1982), “It was an obvious conjecture that transmission between two electrically generating and responsive structures could be electrical,” but there already were experimental data suggesting chemical transmission at the neuromuscular synapse. The distinction between the two modes was clarified in the ensuing decades, with the advent of the neuron doctrine, according to which neurons are independent biological units (reviewed in Eccles, 1961, 1982). Briefly, the preponderance of data obtained at peripheral nervous system junctions was pharmacological and supported the concept of chemical transmission, such as the action of acetylcholine at the heart. However, in the case of the CNS, there wasn’t pharmacological data mimicking synaptic action, and the neuronal responses to applied chemical agents had longer delays than those of the responses evoked by nerve stimulation, leaving room to argue for electrical transmission.

Fatt (1954) reviewed the two general mechanisms that could underlie electrical transmission. The first is a direct connection between the cytoplasms of the two coupled neurons via a low impedance path, with the degree of coupling being determined by the relative sizes of the coupling and “post-junctional” conductances. Although he considered this mode of transmission unlikely, coupling between nerve cells via gap junctions is now well-established, and these synapses can be uni- or bi-directional, depending on the voltage-dependent properties of the channel connexins (see below).

The second is “ephaptic” transmission or coupling via current flow through the extracellular space. This model dates back to experiments by Arvanitaki et al. (1964), who established artificial points of contact between two axons and showed current flow from one element to the next by applying an unbiologically powerful stimulus, the “detonator potential.” While there are numerous examples where the electrical activity of populations of neurons is modulated or biased by local extracellular fields (reviewed by Weiss and Faber, 2010), evidence for field effects that have characteristics analogous to those of chemical synaptic transmission has only been demonstrated in a few model systems. Nevertheless, these effects can be quite powerful. The best known examples involve the Mauthner cell, an identified reticulospinal neuron that triggers an escape behavior in many teleosts, and cerebellar Purkinje cells. In the former, ephaptic inhibition mediated by a specific class of interneurons sets the startle response threshold, and in the latter, it controls Purkinje cell synchrony. According to the ephaptic model, current associated with a presynaptic action potential is “forced” across the postsynaptic membrane because there is a high extracellular impedance in the surrounding neuropil. Thus, ephaptic transmission meets the first requirement listed above, namely, sufficient strength to be physiologically relevant, due to a specialized extracellular structure which is postulated to contribute to a high extracellular resistance. These specializations are known as the axon cap of the Mauthner cell and the pericellular basket, or Pinceau, of Purkinje cells. In the case of speed, suffice it to note that in these well-studied systems there is no delay between the simultaneously recorded presynaptic action potential and the “postsynaptic” field effect. Finally, whether a field effect is excitatory or inhibitory depends upon the direction and magnitude of postsynaptic current flow at the excitable postsynaptic membrane region, as discussed below. Here, we focus on the type of field effect that is analogous to chemical transmission, with identified pre- and postsynaptic elements, and the modulatory effects mediated by synchronous activation of populations of neurons are reviewed elsewhere (Weiss and Faber, 2010).

Interestingly, Eccles, who was a major proponent of electrical transmission in the CNS until he provided, with Fatt (1954), the most compelling evidence for the chemical mode, proposed models for electrical excitation and inhibition in the 1940s ​(Figure 2) which are still relevant today (Eccles, 1946; Brooks and Eccles, 1947). The models for electrical excitation and inhibition are quite straightforward; current from an extracellular source, e.g., the presynaptic axon, depolarizes and hyperpolarizes different regions of the postsynaptic membrane, with the constraints that: (i) the sum of imposed current flowing in across the neuronal membrane equals the sum of the outward current; and (ii) the functional sign of a field effect depends upon the direction of current flow across excitable postsynaptic membrane. The model proposed for electrical excitation postulated that a monophasic presynaptic current entered inexcitable postsynaptic membrane apposed to the synaptic terminal and exited across adjacent excitable membrane, thereby depolarizing the latter (Figure 2A). For electrical inhibition, sign inversion was achieved by interjecting an inhibitory interneuron that is depolarized but not to threshold, with its current in turn hyperpolarizing the inexcitable region of the postsynaptic membrane ​(Figure 2B). Eccles recognized that the current would be excitatory elsewhere and suggested that the extensive neuronal dendritic tree served the function of dissipating the outward excitatory current across a large distributed area of membrane, thereby minimizing its effect on excitation. These models, with the addition of distinguishing effects of membrane capacitance and implications of presynaptic spike waveform, account for most features of ephaptic transmission.

Finally a set of elegant experiments by Katz, Fatt, Miledi and colleagues showed that chemical transmission is mediated by a Ca++-dependent electrically regulated form of release of neurotransmitter packets (Katz, 1969), which in turn are capable of generating an electrical signal in the postsynaptic cell by acting specifically on ligand-gated ion channels known as “receptors” ​(Figure1B, left). It is now recognized that both modes of communication, electrical and chemical, are operative ​(Figure 1B).