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

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).

Theoretically, simple electrical circuits with biologically realistic constraints on the passive and active voltage-dependent properties of neurons, their spatial orientation and the conductivity of the extracellular space could be used to predict whether a single neuron or a group of synchronously active cells generate enough extracellular current to affect the excitability of neighboring cells. That small capacitive and ohmic currents do flow from one cell to the next is not in doubt ​(Figure4). The question is whether the small fraction of the source current that will be channeled transcellularly is large enough to have functional significance? Weiss and Faber (2010) addressed that question by comparing the strengths of local field potentials (LFPs) associated with endogenous electrical activity of normal and epileptogenic hippocampal pyramidal neurons with the strengths of applied fields shown to modify the timing of spike activity, ''in vitro''. The effective applied fields were weaker, consistent with the notion that fields effect rhythmogenesis and neuronal synchrony. This function is most likely exerted in homogeneous CNS structures where a population of neurons have similar morphologies and orientations, such that their currents sum, as for hippocampal and cortical pyramidal cells. Indeed, modeling combined with electrophysiological experiments suggest these modulations of ongoing activity may have functional significance (see, for example, Fröhlich and McCormick, 2010; Anastassiou et al., 2011; Berzhanskaya et al., 2013; Han et al., 2018).

But, can this mechanism also underlie synaptic communication? Contrasting Eccles’ models of ephaptic excitation and inhibition suggests that the former is relatively straightforward and is primarily a function of the parallel or radial alignment of a population of neighboring neurons and the conductivity of the extracellular space, i.e., of the relative impedance and the orientation of the transcellular and extracellular current pathways. Yet, there are no compelling examples of ephaptic excitation mediating a distinct synaptic function with identified pre- and postsynaptic elements. Indeed, it is surprising that the prominent examples of electrical interactions between neurons consistent with a synaptic function are inhibitory. They include the bidirectional inhibition between the teleost Mauthner cell and a class of inhibitory interneurons (Faber and Korn, 1973; Korn and Faber, 1976; Korn et al., 1978), and the connection between cerebellar Basket cells and Purkinje cells (Korn and Axelrad, 1980; Blot and Barbour, 2014). Furthermore, these model systems share structural specializations and physiological properties, lending support to the hypothesis that these examples represent a form of electrical synaptic action.

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).

It is noteworthy that another system with well-studied ephaptic inhibition is the cerebellar pinceau where terminal axons of basket cells form a densely packed sheath around the Purkinje cell initial axon segment. This unusual axonic arrangement of inhibitory basket cells on Purkinje cells can be also considered, as in the Mauthner cell, a synaptic specialization supporting electrical transmission. Blot and Barbour (2014) showed that this ephaptic inhibition could, at very weak fields produced by a spike in a single basket cell, reduce the firing rate of an active Purkinje cell. They postulated that the coupling between cells was due to capacitive current flow, not to resistive current as suggested for the Mauthner cell. However, the time constants of the Mauthner cell and of the inhibitory interneurons are unusually brief, in the range of 100–200 microseconds, and 2 milliseconds, respectively, suggesting resistive coupling is a major portion of the electrical inhibition in that network. Regardless, the speed of coupling in both systems may be one function of electrical inhibitory synapses.

Evidence is slowly accumulating that ephaptic currents generated by single neurons can be detected, and they have been shown to influence neuronal firing patterns in diverse structures, including teleost midbrain (2005), mammalian cortex (Anastassiou et al., 2011), cerebellar cortex (Blot and Barbour, 2014) and snail CNS (Bravarenko et al., 2005). These findings suggest that physiologically relevant ephaptic interactions may be more ubiquitous than appreciated, a prospect supported by formal models of ordered structures, such as olfactory nerve (Bokil et al., 2001) and other olfactory structures (Van der Goes van Naters, 2013) and retina (Byzov and Shura-Bura, 1986; Vroman et al., 2013) but see (Kramer and Davenport, 2015), subject to structural and biophysical constraints, including the properties discussed here.

Despite the predominance of electrical signaling in the nervous system, synaptic communication ubiquitously occurs via the interposition of a chemical messenger, or neurotransmitter, between synaptically-connected cells. Chemical communication is likely an evolutionarily earlier communication strategy, as it occurs between unicellular organisms (Li and Nair, 2012). However, chemical communication between neurons is controlled by and capable of generating electrical signals: evoked transmitter release requires presynaptic depolarization and neurotransmitter receptors generate postsynaptic electrical signals (Sheng et al., 2012). Given such a close interrelationship between electrical signaling and chemical communication, the latter was also called “electrochemical transmission” (Llinás, 2001).

Despite their dependence on electricity, these three forms of communication co-exist because their individual properties differentially contribute to the processing of information within circuits. Chemical synapses, in addition to having receptors that gate ligand-bound ion channels capable of generating changes in the membrane potential of the cell following activation, have metabotropic receptors capable of activating a variety of biochemical cascades. Activation of biochemical cascades can occur following the binding of neurotransmitter to either ionotropic and metabotropic receptors and could lead to long-term modification of synaptic and/or cellular properties and induction of gene expression (Sheng et al., 2012). Thus, chemical synapses have the ability to transform a presynaptic signal into a variety of spatial and temporal patterns, an adaptive property that contributes to a great extent to the diversity of synaptic communication in the brain.

In contrast, the lack of a measurable synaptic delay implies that electrical transmission may be better adapted to ensure fast processing of signals through neural networks. While the two forms of electrical transmission have in common a high-speed of synaptic communication they however seem to serve different roles in communication, from the network point of view. There are, so far, fewer examples of electrical communication mediated by electric fields and as a result, less is known of the underlying mechanism. It is, however, known that its actions are localized on critical subcellular locations, such as the neuron’s initial segment. This feature allows synapses mediated by electric fields to convey exquisite timing information to decision-making cells within a circuit. Because of its speed, electrical transmission mediated by fields was shown to be critical in the processing of auditory information by the circuits that control the excitability of the teleost Mauthner cell (Weiss et al., 2008), and this mechanism is likely to play similar roles in controlling the activation of Purkinje neurons by cerebellar circuits (Blot and Barbour, 2014). In contrast, electrical synapses mediated by gap junctions are more widely distributed within neural networks and, a result of their bidirectionality, promote coordinated network activity by allowing computation of subthreshold variations of membrane potential between electrically-coupled cells. While promoting electrical synchronization is the signature property of gap junction mediated electrical synapses, their functional roles also include desynchronization, enhancement of signal to noise ratio, and coincidence detection, amongst others (reviewed in Connors, 2017).

Finally, the functional value of each form of transmission has its unique valence, which cannot be accomplished by the other. This functional categorization, is emphasized by the existence of mixed transmission at synaptic contacts at which chemical and electrical transmission, mediated by either gap junctions (Furshpan, 1964) or electric fields (Korn and Faber, 1976), act in concert to secure communication with a postsynaptic cell.