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

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).

From the functional point of view, gap junction channels most commonly operate electrically as ohmic resistors, providing bidirectional communication for electrical signals between two or more cells ​(Figure3B). Currents underlying action potentials in a presynaptic cell can directly flow via the gap junction to the postsynaptic cell, generating “electrical synaptic potentials” or “coupling potentials,” which also are known as “spikelets” ​(Figure1B, middle). Not only currents underlying action potentials but also those responsible for subthreshold signals such as synaptic potentials of either depolarizing or hyperpolarizing nature can spread to the postsynaptic cell to generate a coupling potential ​(Figure3B). The strength or weight of the postsynaptic cell’s response and the passive properties of the coupled cells are largely interdependent (Bennett, 1966; Getting, 1974). Accordingly, the amplitude of the coupling potential is determined not only by the conductance of the gap junction channels but also by the input resistance of the postsynaptic cell (see Bennett, 1966). In addition, the passive properties of the postsynaptic cell impose limitations to the transmission of presynaptic signals, depending on their duration. Short lasting signals such as action potentials are more attenuated than longer lasting signals such as synaptic potentials or afterhyperpolarizations due to the filtering properties of the postsynaptic membrane which are reflected by the membrane “time constant” of the cell (a parameter determined by the product of the cell’s resistance and capacitance that expresses how rapidly the resting membrane potential of the cell can be modified by a given current). As a result, the “coupling coefficient,” a measure of the synaptic strength, defined as the ratio between the amplitude of the postsynaptic coupling potential and that of the presynaptic signal, can be dramatically different for signals with different time courses.

Rather than simple conduits the gap junction channels themselves contribute to electrical communication. The molecular composition and properties of the gap junction intercellular channel have been shown to endow electrical transmission with voltage-dependent properties. Hemichannels that contribute to form the intercellular channel can be made of the same or different connexin or innexin proteins. Intercellular channels formed by hemichannels made of the same protein are called “homotypic,” whereas channels formed by hemichannels made of different proteins are called “heterotypic”  ​(Figure3A, inset). Molecular differences between the involved hemichannels are commonly associated with rectification of electrical transmission (Barrio et al., 1991; Verselis et al., 1994) and, providing support for such prediction, this association has been observed for both connexin (Rash et al., 2013) and innexin-based electrical synapses (Phelan et al., 2008). Rectification refers to the ability of electrical currents to preferentially flow in one direction, in other words, they behave as electrical diodes. However, this property critically depends on the polarity of the signal. As observed in the crayfish giant fiber synapses (Furshpan and Potter, 1959; Giaume et al., 1987), depolarizations can travel from the presynaptic to the postsynaptic side but not in the opposite directions, and hyperpolarizations can travel from the postsynaptic to the presynaptic side but not the other direction ​(Figure3C). The polarized features of electrical transmission suggest the existence of a voltage-sensitive mechanism underlying this property. Several mechanisms were proposed to contribute to steep electrical rectification of gap junction channels, such as that observed in crayfish. Electrical rectification can be a consequence of the separation of fixed positive and negative charges at opposite ends of heterotypic gap junction channels, configuring a “p-n junction,” which results from asymmetries in the molecular composition of the hemichannels that form the intercellular channel (Oh et al., 1999). Alternatively, electrical rectification could result from the presence of charged cytosolic factors which alter channel conductance, such as Mg++ (Palacios-Prado et al., 2013, 2014) and spermine (Musa et al., 2004), which were to shown to interact with the gap junction channel. Combinations of these or more factors are likely to contribute to this striking voltage-dependent feature of some electrical synapses (reviewed in Palacios-Prado et al., 2014). Finally, the conductance of neuronal gap junctions was shown to be target of numerous regulatory mechanisms that endow electrical synapses with plastic properties equivalent to those observed at chemical synapses (reviewed in Pereda et al., 2013; O’Brien, 2014, 2017; Pereda, 2014).

The Mauthner cell is a large identifiable midbrain neuron found in many teleosts, and it has a number of morphological specializations that make it an unique model system. Furukawa and Furshpan (1963) discovered the first example of electrical inhibition when comparing the intra- and extracellular potentials evoked in the axon cap by antidromic stimulation of this neuron’s axon—as noted, the axon cap is a dense neuropil surrounding the initial segment of the Mauthner cell axon. First, the antidromic action potential in the extracellular space (Ve) is very large and negative, as much as −40 mV, and the corresponding spike height recorded intra-axonally (Vi) at the site of spike initiation is smaller, ~+50 mV, so that the full transmembrane spike height, calculated as the difference between the intra- and extracellular responses, i.e., Vi − Ve, ~+90 mv (Furshpan and Furukawa, 1962). This observation of such a large extracellular potential associated with one neuron’s action potential suggested a high resistance barrier to extracellular current, and it has been proposed that this property is a consequence of the structure of the axon cap: swelling of interneuron axons at the edge of the cap, and close proximity to a densely packed ring of glia at the same boundary, known as the “canestro” or “basket” of Beccari (1907). These morphological features represent cellular specializations that support electrical communication and, therefore, may be analogous to structural specializations found at chemical synapses. Furthermore, the antidromic spike was succeeded by an extracellular positivity, which they named the Extrinsic Hyperpolarizing Potential (EHP) since it was larger than its intracellular representation, and, thus the same calculation showed that (Vi - Ve) < 0 and that the EHP is inhibitory. It was shown subsequently that the EHP was generated by impulses in a class of inhibitory interneurons that mediate feedback and feedforward inhibition of the Mauthner cell and that the evoked inhibition has two components, with a classical glycinergic inhibition of the Mauthner cell following the electrical component by ~0.5 ms (Figure 4A; Korn and Faber, 1976). In the case of the feedforward circuit, the short latency allows electrical inhibition to occur synchronously with excitation, thereby limiting the duration of the decision-making window in processing information by the Mauthner cell. Thus, these connections mediate mixed, electrical and chemical, synaptic actions ​(Figure 4A).

Additional specializations support the notion that electrical inhibition is physiological and functionally relevant. For example, the presynaptic spike in the inhibitory interneurons propagates passively within the cap, where the afferent axon loses its myelination. Consequently, the local field is monophasic, increasing its effectiveness. The EHP, which acts as an extracellular anode, that is, as an external current source, can be as large as 20 mV. Paired pre- and postsynaptic recordings show that the contribution of a single interneuron is about 0.4 mV per presynaptic spike, suggesting about 50 interneurons discharge synchronously following antidromic stimulation This is a powerful population effect that shuts down the Mauthner cell for 10’s of milliseconds. However, as noted above, these neurons are also excited in a feedforward circuit that relays auditory information to the Mauthner cell. In this case the EHP is graded as a function of stimulus strength, and it serves to set the threshold of a sound-evoked behavior, the escape response: when a sound-evoked EHP is canceled by an applied cathodal current in the axon cap, the underlying subthreshold EPSP is converted to suprathreshold, triggering Mauthner cell activation (Weiss et al., 2008).

Other factors which influence the operation of electrical inhibition include the orientation of the involved neurons and the distribution of excitable membrane relative to extracellular current sources and sinks. The Mauthner cell system is an ideal model for extracting mechanistic features, especially since there is reciprocal inhibition in the network, that is, the interneurons are inhibited by the Mauthner cell action currents (electric currents that originate from variations of potential during neural activity). Figures 4B, Ccontrasts the two examples. In both cases, the inhibitory current is channeled inward across excitable membrane, namely the Mauthner axon initial segmenti (Figure 4B) or the last node, or heminode, of the inhibitory interneuron’s axon ​(Figure 4C). Conversely, it exits the target through inexcitable membrane, that is, across soma-dendritic- or axon terminal membrane, respectively. Thus, if the distribution of excitable or inexcitable membrane were altered, the sign and magnitude of the ephaptic action would be altered accordingly. These considerations pertain to other networks as well, as discussed below.