Which of the following would increase conduction velocity of an action potential in axon?

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21.3.17 Significance of Slow IPSPs in the Integrated System

A reduction in the membrane resistance and excitability of the somal membranes, together with membrane hyperpolarization during the slow IPSPs, decreases the probability of action potential discharge. The probability that the somal membrane will be fired by spikes invading the soma electrotonically from its neurites or during fast excitatory synaptic input is reduced during slow IPSPs (Figures 21.4 and 21.6). This influence is the inverse of the slow EPSP and acts to close the gate for transfer of spike information across the multipolar soma of AH neurons (Figure 21.4E). Slow synaptic inhibition probably functions to terminate the excitatory state of slow synaptic excitation and reestablish the low excitability state in the ganglion cell soma of AH neurons. In the intact animal, there may also be inhibitory substances of endocrine or paracrine origin that function in particular situations to lock the somal membranes in a low excitability state.

Functional Significance of Slow IPSPs

A reduction in the membrane resistance and excitability of the somal membranes, together with membrane hyperpolarization during the slow IPSPs, decrease the probability of action potential discharge. The probability is reduced that the somal membrane will be fired during electrotonic invasion by spikes in the initial axonal segment or during excitatory synaptic input (see Figs. 12-5 and 12-9). This influence is the inverse of the slow EPSP and acts to close the gate for transfer of spike information across the multipolar soma of AH neurons.

Slow synaptic inhibition probably functions to terminate the excitatory state of slow synaptic excitation and reestablish the low excitability state in the ganglion cell soma of AH neurons. This may be a step in the control of sequentially occurring motor events such as the conversion from inhibition to excitation in the circular muscle of an intestinal segment during propagation of propulsive peristalsis. In the intact animal, there may also be inhibitory substances of endocrine or paracrine origin that function in particular situations to lock the somal membranes in a low excitability state.

High Specific Membrane Resistance

A second key property is the specific membrane resistance (Rm) of the dendritic membrane. Traditionally, the argument was that if Rm is relatively low, the characteristic length of the dendrites will be relatively short, the electrotonic length will be correspondingly long, and synaptic potentials will therefore decrement sharply in spreading toward the axon hillock. However, as discussed in Chapter 4, intracellular recordings indicated that Rm is sufficiently high that the electrotonic lengths of most dendrites are in the range of 1–2 (Johnston and Wu, 1995) and recent patch recordings suggest much higher Rm values, indicating electrotonic lengths less than 1. Thus, a relatively high Rm seems adequate for close electrotonic linkage, at least in the steady state (Fig. 17.5B).

4.2 Retrograde flow of adhesion components in the integrin–actin linkage

Adhesions are sites of traction where the forces arising from membrane resistance to actin polymerization and myosin-mediated contraction are transmitted to the substratum. In the absence of a firm linkage between actin and the substratum, these forces lead to retrograde flow of actin (opposite the direction of polymerization) as new actin monomers are added or the filaments are contracted and moved toward the cell center. The presence of actin retrograde flow suggests that this linkage might not always be efficient and points to the present of a molecular “clutch” with varying efficiency (Mitchison & Kirschner, 1988; Ponti, Machacek, Gupton, Waterman-Storer, & Danuser, 2004). Brown et al. (2006) used spatiotemporal image correlation spectroscopy to address this issue. Single-channel spatiotemporal ACFs were calculated from image time series of cells coexpressing RFP-actin and GFP-tagged variants of paxillin, α5-integrin, talin, FAK, vinculin, and α-actinin. The magnitude and direction of flow of the individual molecules were estimated from the temporal displacement of the peak of the spatial autocorrelation. An example of a spatial map of the flow of paxillin–GFP and RFP–actin is presented in Fig. 6.5A. The relative magnitude and direction of the velocity vectors for the various adhesion components relative to actin revealed a differential correlation between certain adhesion and actin retrograde velocities (Fig. 6.5B). The nature of the correlation was cell-type dependent: highly contractile cells, like MEF or 3T3 cells, showed a stronger coupling between adhesion molecules and actin, whereas CHO cells, which are less contractile, showed reduced coupling (Fig. 6.5B). Thus, it appears that the forces on adhesions are modulated by the efficiency of the integrin–actin linkage to retrograde forces. As the force on adhesions feeds back to dictate adhesion size, organization, and signaling, this clutch has major ramifications for the cell.

Myelin and Nodes of Ranvier

Action potential conduction velocity can be enhanced by indirectly increasing the membrane resistance (Rm) with an insulating material that wraps around the axon. This insulating wrap is called myelin, and is made from the membrane of glial cells. In the central nervous system oligodendrocytes wrap myelin around axons, whereas in the peripheral nervous system Schwann cells form the myelin wrap (see Fig. 4.17). These specialized glial cells wrap around the axons many times with their lipid-rich membrane, which acts as an insulator, increasing Rm.

Each glial cell only covers a small length of the axon, with a small gap between myelinated segments. Each gap is called a node of Ranvier. In myelinated axons, the action potential can conduct passively along the axon under the sections of myelin sheath, and is only regenerated at the nodes of Ranvier. In general, there are no voltage-gated channels under the myelin, while the nodes of Ranvier have a high concentration of voltage-gated sodium and potassium channels for effective action potential generation (see Figs. 4.16 and 4.18). With this structural organization, myelinated axons can rapidly conduct action potentials over long distances. This form of action potential conduction is called saltatory conduction, meaning “conduction that proceeds by leaps,” because action potentials effectively “leap” along the axon from node to node. This is in contrast to action potential conduction in unmyelinated axons, which proceeds more slowly, both because such axons have a lower Rm and because action potentials need to be regenerated at each patch of membrane along the entire length of the axon.

Sensory axons that transmit pain and temperature information are unmyelinated and have an action potential conduction velocity of 0.5–2 m/s (or 1–5 miles/h, about as fast as you might walk or run). In contrast, the myelinated axons that connect spinal motor neurons with skeletal muscle can conduct action potentials at 80–120 m/s (or 180–250 miles/h, about as fast as a race car drives). Interestingly, the length of each myelin segment appears to vary between different types of axons and may be regulated to optimize action potential timing within systems where such fine-tuning is essential for information processing (e.g., the auditory system; see Ford et al., 2015).

Ionic Basis of Early Afterdepolarizations

The plateau of the action potential is a time of high membrane resistance, when there is little current flow. Consequently, small changes in repolarizing or depolarizing currents can have profound effects on the action potential duration and profile. Normally, during phases 2 and 3, the net membrane current is outward. Any factor that transiently shifts the net current in the inward direction can lead to EAD. Such a shift can arise from blockage of the outward current, carried by Na+ or Ca2+ at that time, or enhancement of the inward current, mostly carried by K+ at that time.1

EADs have been classified as phase 2 (occurring at the plateau level of membrane potential) and phase 3 (occurring during phase 3 of repolarization; see Fig. 1-4). The ionic mechanisms of phase 2 and 3 EADs and the upstrokes of the action potentials they elicit can differ.1,8,28 At the depolarized membrane voltages of phase 2, the Na+ current is inactivated and EADs can result from reactivation of the L-type Ca2+ current. EADs occurring late in repolarization occur at membrane potentials more negative than −60 mV in atrial, ventricular, or Purkinje cells that have normal resting potentials. Normally, a net outward membrane current shifts the membrane potential progressively in a negative direction during phase 3 repolarization of the action potential. Despite less data, it has been suggested that current through the Na+-Ca2+ exchanger and possibly the Na+ current can participate in the activation of phase 3 EADs.

The upstrokes of the action potentials elicited by phase 2 and phase 3 EADs also differ.1 Phase 2 EAD-triggered action potential upstrokes are exclusively mediated by Ca2+ currents. Even if these triggered action potential do not propagate, they can substantially exaggerate heterogeneity of the time course of repolarization of the action potential (a key substrate for reentry), because EADs occur more readily in some regions (e.g., Purkinje, mid-LV myocardium, RVOT epicardium) than others (e.g., LV epicardium, endocardium). Action potentials triggered by phase 3 EADs arise from more negative membrane voltages. Therefore, the upstrokes can be caused by Na+ and Ca2+ currents and are more likely to propagate.3

Under certain conditions, when an EAD is large enough, the decrease in membrane potential leads to an increase in net inward (depolarizing) current, and a second upstroke or an action potential is triggered before complete repolarization of the first. The triggered action potential also can be followed by other action potentials, all occurring at the low level of membrane potential characteristic of the plateau or at the higher level of membrane potential of later phase 3. The sustained rhythmic activity can continue for a variable number of impulses and terminates when repolarization of the initiating action potential returns membrane potential to a high level. As repolarization occurs, the rate of the triggered rhythm slows because the rate is dependent on the level of membrane potential. Sometimes repolarization to the high level of membrane potential may not occur, and membrane potential can remain at the plateau level or at a level intermediate between the plateau level and the resting potential. The sustained rhythmic activity then can continue at the reduced level of membrane potential and assumes the characteristics of abnormal automaticity. However, in contrast to automatic rhythms, without the initiating action potential, there could be no triggered action potentials.8

The ability of the triggered action potentials to propagate is related to the level of membrane potential at which the triggered action potentials occur.8,44,45 The more negative the membrane potential, the more fast Na+ channels are available for activation, the greater the influx of Na+ into the cell during phase 0, and the higher the conduction velocity. At more positive membrane potentials of the plateau (phase 2) and early during phase 3, most fast Na+ channels are still inactivated, and the triggered action potentials most likely have upstrokes caused by the inward L-type Ca2+ current. Therefore, those triggered action potentials have slow upstrokes and are less able to propagate.3

A fundamental condition that underlies the development of EADs is action potential prolongation, which is manifest on the surface electrocardiogram (ECG) by QT prolongation. Hypokalemia, hypomagnesemia, bradycardia, and drugs can predispose to the formation of EADs, invariably in the context of prolonging the action potential duration; drugs are the most common cause.8 Class IA and III antiarrhythmic agents prolong the action potential duration and the QT interval, effects intended to be therapeutic but frequently causing proarrhythmia. Noncardiac drugs such as some phenothiazines, some nonsedating antihistamines, and some antibiotics can also prolong the action potential duration and predispose to EAD-mediated triggered arrhythmias, particularly when there is associated hypokalemia, bradycardia, or both.46 Decreased extracellular K+ concentration paradoxically decreases some membrane K+ currents (particularly the delayed rectifier K+ current, IKr) in the ventricular myocyte, explaining why hypokalemia causes action potential prolongation and EADs. EAD-mediated triggered activity likely underlies initiation of the characteristic polymorphic VT, torsades de pointes, seen in patients with congenital and acquired forms of long-QT syndrome. Although the genesis of ventricular arrhythmias in these patients is still unclear, marked transmural dispersion of repolarization can create a vulnerable window for development of reentry. EADs arising from these regions can underlie the premature complexes that initiate or perpetuate the tachycardia.1,3,47 Structural heart disease such as cardiac hypertrophy and failure can also delay ventricular repolarization—so-called electrical remodeling—and predispose arrhythmias related to abnormalities of repolarization.48 The abnormalities of repolarization in hypertrophy and failure are often magnified by concomitant drug therapy or electrolyte disturbances.

EADs are opposed by activators of ATP-dependent K+ channels (pinacidil, chromakalim), magnesium, alpha-adrenergic blockade, tetrodotoxin, nitrendipine, and antiarrhythmic drugs that shorten action potential (e.g., lidocaine and mexilitine).49,50 Alpha-adrenergic stimulation can exacerbate EADs.51

It has been traditionally thought that unlike DADs, EADs do not depend on a rise in intracellular Ca2+; instead, action potential prolongation and reactivation of depolarizing currents are fundamental to their production. More recent experimental evidence has suggested a previously unappreciated interrelationship between intracellular Ca2+ loading and EADs. Cytosolic Ca2+ levels can increase when action potentials are prolonged, which in turn appears to enhance L-type Ca2+ current (possibly via calcium-calmodulin kinase activation), further prolonging the action potential duration as well as providing the inward current driving EADs. Intracellular Ca2+ loading by action potential prolongation can also enhance the likelihood of DADs. The interrelationship among intracellular Ca2+, DADs, and EADs can be one explanation for the susceptibility of hearts that are Ca2+-loaded (e.g., in ischemia or congestive heart failure) to develop arrhythmias, particularly on exposure to action potential–prolonging drugs.

Ionic Basis of Early Afterdepolarizations

The plateau of the action potential is a time of high membrane resistance (i.e., membrane conductance to all ions falls to rather low values), when there is little current flow. Consequently, small changes in repolarizing or depolarizing currents can have profound effects on the action potential duration and profile. Normally, during phases 2 and 3, the net membrane current is outward. Any factor that transiently shifts the net current in the inward direction can potentially overcome and reverse repolarization and lead to EADs. Such a shift can arise from blockage of the outward current, carried by Na+ or Ca2+ at that time, or enhancement of the inward current, mostly carried by K+ at that time.1

EADs have been classified as phase 2 (occurring at the plateau level of membrane potential) and phase 3 (occurring during phase 3 of repolarization; see Fig. 3-4). The ionic mechanisms of phase 2 and phase 3 EADs and the upstrokes of the action potentials they elicit can differ.1 At the depolarized membrane voltages of phase 2, Na+ channels are inactivated; hence, the ICaL and Na+-Ca2+ exchanger current are the major currents potentially responsible for EADs. Voltage steady-state activation and inactivation of the L-type Ca2+ channels are sigmoidal, with an activation range over –40 to +10 mV (with a half-activation potential near –15 mV) and a half-inactivation potential near –35 mV. However, a relief of inactivation for voltages positive to 0 mV leads to a U-shaped voltage curve for steady-state inactivation. Overlap of the steady-state voltage-dependent inactivation and activation relations defines a “window” current near the action potential plateau, within which transitions from closed and open states can occur. As the action potential repolarizes into the window region, ICaL increases and can potentially be sufficient to reverse repolarization, thus generating the EAD upstroke (Fig. 3-7).23

The cardiac Na+-Ca2+ exchanger exchanges three Na+ ions for one Ca2+ ion; the direction is dependent on the Na+ and Ca2+ concentrations on the two sides of the membrane and the transmembrane potential difference. When operating in forward mode, this exchanger generates a net Na+ influx, thereby resisting repolarization. The increase in the window ICaL further increases the Na+-Ca2+ exchanger, thus possibly facilitating EAD formation and increasing the probability of an EAD-triggered action potential.23

EADs occurring late in repolarization develop at membrane potentials more negative than −60 mV in atrial, ventricular, or Purkinje cells that have normal resting potentials. Normally, a net outward membrane current shifts the membrane potential progressively in a negative direction during phase 3 repolarization of the action potential. Despite fewer data, it has been suggested that current through the Na+-Ca2+ exchanger and possibly the INa can participate in the activation of phase 3 EADs. Nevertheless, this concept was questioned by a study suggesting that phase 2 EADs appear to be responsible for inducing phase 3 EADs through electrotonic interactions and that a large voltage gradient related to heterogeneous repolarization is essential for phase 3 EADs.23,24

The upstrokes of the action potentials elicited by phase 2 and phase 3 EADs also differ.1 Phase 2 EAD-triggered action potential upstrokes are exclusively mediated by Ca2+ currents. Even when these triggered action potentials do not propagate, they can substantially exaggerate heterogeneity of the time course of repolarization of the action potential (a key substrate for reentry), because EADs occur more readily in some regions (e.g., Purkinje fibers, mid left ventricular myocardium, right ventricular outflow tract epicardium) than others (e.g., left ventricular epicardium, endocardium). Action potentials triggered by phase 3 EADs arise from more negative membrane voltages. Therefore, the upstrokes can be caused by Na+ and Ca2+ currents and are more likely to propagate.

Under certain conditions, when an EAD is large enough, the decrease in membrane potential leads to an increase in net inward (depolarizing) current, and a second upstroke or an action potential is triggered before complete repolarization of the first. The triggered action potential also can be followed by other action potentials, all occurring at the low level of membrane potential characteristic of the plateau or at the higher level of membrane potential of later phase 3 (Fig. 3-8). The sustained rhythmic activity can continue for a variable number of impulses and terminates when repolarization of the initiating action potential returns membrane potential to a high level. As repolarization occurs, the rate of the triggered rhythm slows because the rate is dependent on the level of membrane potential. Sometimes repolarization to the high level of membrane potential may not occur, and membrane potential can remain at the plateau level or at a level intermediate between the plateau level and the resting potential. The sustained rhythmic activity then can continue at the reduced level of membrane potential and assumes the characteristics of abnormal automaticity. However, in contrast to automatic rhythms, without the initiating action potential, there can be no triggered action potentials.

The ability of the triggered action potentials to propagate is related to the level of membrane potential at which the triggered action potential occurs. The more negative the membrane potential is, the more Na+ channels are available for activation, the greater the influx of Na+ into the cell during phase 0, and the higher the conduction velocity. At more positive membrane potentials of the plateau (phase 2) and early during phase 3, most Na+ channels are still inactivated, and the triggered action potentials most likely have upstrokes caused by the inward ICaL. Therefore, those triggered action potentials have slow upstrokes and are less able to propagate. Increased dispersion of repolarization facilitates the ability of phase 2 EADs to trigger propagating ventricular responses.24

A fundamental condition that underlies the development of EADs is action potential prolongation, which is manifest on the surface ECG by QT prolongation. Hypokalemia, hypomagnesemia, bradycardia, and drugs can predispose to the formation of EADs, invariably in the context of prolonging the action potential duration; drugs are the most common cause. Class IA and III antiarrhythmic agents prolong the action potential duration and the QT interval, effects intended to be therapeutic but frequently causing proarrhythmia. Noncardiac drugs such as some phenothiazines, some nonsedating antihistamines, and some antibiotics can also prolong the action potential duration and predispose to EAD-mediated triggered arrhythmias, particularly when there is associated hypokalemia, bradycardia, or both. Decreased extracellular K+ concentration paradoxically decreases some membrane IK (particularly the IKr) in the ventricular myocyte. This finding explains why hypokalemia causes action potential prolongation and EADs. EAD-mediated triggered activity likely underlies initiation of the characteristic polymorphic VT, torsades de pointes, seen in patients with congenital and acquired forms of long QT syndrome (see Chapter 31). Although the genesis of ventricular arrhythmias in these patients is still unclear, marked transmural dispersion of repolarization can create a vulnerable window for development of reentry. EADs arising from these regions can underlie the premature complexes that initiate or perpetuate the tachycardia.1 Structural heart disease such as cardiac hypertrophy and failure can also delay ventricular repolarization—so-called electrical remodeling—and predispose to arrhythmias related to abnormalities of repolarization. The abnormalities of repolarization in hypertrophy and failure are often magnified by concomitant drug therapy or electrolyte disturbances.

EADs are opposed by ATP-dependent K+ channel (IKATP) openers (pinacidil, cromakalim, rimakalim, and nicorandil), magnesium, alpha-adrenergic blockade, tetrodotoxin, nitrendipine, and antiarrhythmic drugs that shorten action potential (e.g., lidocaine and mexiletine). Alpha-adrenergic stimulation can exacerbate EADs.

It was traditionally thought that unlike DADs, EADs do not depend on a rise in intracellular Ca2+; instead, action potential prolongation and reactivation of depolarizing currents are fundamental to their production. More recent experimental evidence suggested a previously unappreciated interrelationship between intracellular Ca2+ loading and EADs. Cytosolic Ca2+ levels can increase when action potentials are prolonged. This situation, in turn, appears to enhance ICaL (possibly via Ca2+-calmodulin kinase activation), thus further prolonging the action potential duration as well as providing the inward current driving EADs. Intracellular Ca2+ loading by action potential prolongation can also enhance the likelihood of DADs. The interrelationship among intracellular Ca2+, DADs, and EADs can be one explanation for the susceptibility of hearts that are Ca2+ loaded (e.g., in ischemia or congestive heart failure) to develop arrhythmias, particularly on exposure to action potential–prolonging drugs.

Electrotonic Spread Depends on the Diameter of a Process

The length constant (λ) depends not only on the internal and membrane resistance, but also on the diameter of a process. Thus, from the relations between rm and Rm, and ri and Ri, discussed in the preceding section,

(17.3)λ=rmri=RmRi⋅d4

Neuronal processes vary widely in diameter. In the mammalian nervous system, the thinnest processes are the distal branches of dendrites and the necks of some dendritic spines; these processes may have diameters of only 0.1 μm or less. In contrast, the largest dendritic trunks of mammalian neurons may have diameters as large as 20 to 25 μm. This means that the range of diameters is approximately three orders of magnitude (1,000-fold). Note, again, that λ varies with the square root of d; thus, for a 10-fold change in diameter, the change in λ is only about 3-fold.

45.2.3 Basic Physiological Properties of Oligodendrocyte Lineage Cells

Neurons and glial cells display very distinct electrophysiological properties. Neurons have fairly high membrane resistances (~ 100–300 MΩs), resting potentials around − 70 mV, and express a particular complement of voltage-gated sodium (NaV) and potassium (Kv) channels that allow action potential firing upon membrane depolarization (Purves et al., 2001). In contrast, most glial cells in the CNS, such as astrocytes, have low membrane resistances (10–50 MΩ), resting potentials near the equilibrium potential for potassium (EK = − 90 to − 100 mV), and are inexcitable or do not fire action potentials when depolarized (Bergles and Jahr, 1997; Ransom and Sontheimer, 1992).

The proteoglycan ‘NG2’ was originally identified as an antigen expressed by cultured brain cells that exhibited both ‘neuronal’ and ‘glial’ properties (Wilson et al., 1981), and this description is consistent with the hybrid physiological characteristics of OPCs. Like astrocytes, OPCs have resting potentials near EK (− 90 mV) (Lin and Bergles, 2002) and are generally not observed to fire action potentials (Bergles et al., 2000; Chittajallu et al., 2004; De Biase et al., 2010; Ge et al., 2006; Kukley et al., 2007; Lin et al., 2005; Ziskin et al., 2007), although there may be some differences between OPCs in rat and mouse. Nonetheless, like neurons, OPCs express NaV and Kv channels that are activated during depolarization. For this reason, these cells have been referred to as ‘complex’ astrocytes because of their nonlinear response to membrane depolarization (Jabs et al., 2005; Matthias et al., 2003; Wallraff et al., 2004), which contrasts sharply with the passive, linear responses of astrocytes to the same stimulation. OPCs are similar to neurons in two additional ways: they have relatively high membrane resistances (100 MΩ–1 GΩ) and, most strikingly, they form synapses with neurons (Bergles et al., 2000).

As OPCs differentiate into pre-oligodendrocytes, their signature electrophysiological features are rapidly altered. Membrane capacitance (Cm), which reflects membrane surface area, changes from being relatively small (15–30 pF Cm) to quite large (50–150 pF Cm) (Chittajallu et al., 2005; De Biase et al., 2010; Kukley et al., 2010) as the cell acquires the highly branched morphology typical of pre-oligodendrocytes. Synaptic communication with neurons ceases, voltage-activated conductances, including NaV channels, are rapidly downregulated (De Biase et al., 2010; Kukley et al., 2010), and the membrane resistance increases transiently. As pre-oligodendrocytes begin to myelinate surrounding axons, membrane resistance plummets (10–40 MΩ) and the resting potential shifts to more positive values (− 60 to − 40 mV), reflecting dramatic changes in the expression of surface ion channels (Chittajallu et al., 2005; De Biase et al., 2010; Kukley et al., 2010). These rapid changes highlight that, although they belong to the same lineage, OPCs, pre-oligodendrocytes, and mature oligodendrocytes have very distinct physiological properties.

36.2.3 Physiological properties of oligodendrocyte lineage cells

Neurons and glial cells display very distinct electrophysiological properties. Neurons have fairly high membrane resistances (∼100–300 MΩs), resting potentials around −70 mV and express a particular complement of voltage-gated sodium (Nav) and potassium (Kv) channels that allow action potential firing upon membrane depolarization (Purves et al., 2001). In contrast, most glial cells in the CNS, such as astrocytes, have low membrane resistances (10–50 MΩ), resting potentials near the equilibrium potential for potassium (EK = −90 to −100 mV), and are inexcitable or do not fire action potentials when depolarized (Ransom and Sontheimer, 1992; Bergles and Jahr, 1997).

The chondroitin sulfate proteoglycan “NG2” was originally identified as an antigen expressed by cultured brain cells that exhibited both “neuronal” and “glial” properties (Wilson et al., 1981), and this description is consistent with the hybrid physiological characteristics of OPCs. OPCs were initially referred to as “complex” astrocytes because of their nonlinear response to membrane depolarization (Matthias et al., 2003; Wallraff et al., 2004; Jabs et al., 2005), which contrasts sharply with the passive, linear responses of astrocytes to the same stimulation. Like astrocytes, OPCs have resting potentials near EK (−90 mV) (Lin and Bergles, 2002) and do not fire regenerative action potentials (Bergles et al., 2000; Chittajallu et al., 2004; Lin et al., 2005; Ge et al., 2006; Kukley et al., 2007; Ziskin et al., 2007; De Biase et al., 2010), although some OPCs and premyelinating oligodendrocytes in both gray and white matter have been shown to elicit all-or-nothing Nav and Kv channel-dependent spikes when strongly depolarized (Chittajallu et al., 2004; Káradóttir et al., 2008; Ge et al., 2009; Clarke et al., 2012; Berret et al., 2017), though these events are typically small in amplitude and repetitive firing is not sustained. With high thresholds, small amplitudes, and slow kinetics, these “spikes” are dissimilar to neuronal action potentials and spontaneous generation of these events has not been reported, though in vivo recordings from OPCs have not yet been performed.

Transcriptional sequencing methods (see next section) have revealed that OPCs express a diverse complement of ion channels (see Larson et al., 2016 for a detailed review), including a heterogeneous group of Nav channels likely contributing to the unique current-to-voltage relationship exhibited by OPCs, which cannot be explained by any individual Nav channel subtype (Xie et al., 2007). OPCs have relatively low expression of voltage-gated calcium channels, and a complex array of inwardly rectifying potassium channels, with Kir4.1 (KCNJ10) the highest expressed. OPCs are similar to neurons in two additional ways: they have relatively high membrane resistances (100 MΩ–1 GΩ) and, most strikingly, they form synapses with neurons, where they serve as the postsynaptic partner (Bergles et al., 2000).

As OPCs differentiate into premyelinating oligodendrocytes, their signature electrophysiological features are rapidly altered. Membrane capacitance (Cm), which reflects membrane surface area, increases from 15–30 pF to 50–150 pF (Chittajallu et al., 2005; De Biase et al., 2010; Kukley et al., 2010) as the cell acquires the highly branched morphology typical of premyelinating oligodendrocytes. Synaptic communication with neurons ceases, voltage-activated conductances, including Nav channels, are rapidly downregulated (De Biase et al., 2010; Kukley et al., 2010), and the membrane resistance increases transiently. As newly formed oligodendrocytes begin to myelinate surrounding axons, membrane resistance plummets (10–40 MΩ) and the resting potential shifts to more positive values (−60 to −40 mV), reflecting dramatic changes in the expression of surface ion channels (Chittajallu et al., 2005; De Biase et al., 2010; Kukley et al., 2010). In fact, transcriptional expression data show a dramatic reduction in the levels of expressed ion channel and neurotransmitter receptor genes from OPC to mature oligodendrocytes (genes with ≥2 FPKM: 41% in OPCs vs. 14% in mature oligodendrocytes) (Larson et al., 2016). These rapid changes highlight that, although they belong to the same lineage, OPCs, premyelinating oligodendrocytes, and mature oligodendrocytes have distinct physiological properties. However, the timing of these changes in different CNS regions may vary. For example, in the brainstem medial nucleus of the trapezoid body, some premyelinating oligodendrocytes continue to exhibit transient sodium-dependent “spikes,” which have been implicated in controlling their maturation (Berret et al., 2017).