Neurobiology: Driving Forces, Membrane Potentials, and Action Potential Biophysics

Foundations of Electrical Signaling & Passive Membrane Properties

• The organization of the nervous system follows a continuous hierarchy across spatial and functional scales:

  • Genes dictate the expression of channel and receptor proteins.

  • Proteins embed within neuronal and glial cell membranes to establish excitability.

  • Cells assemble into complex, interconnected synaptic circuits.

  • Circuits coordinate systemic physiological functions, cognitive processes, and animal behaviors.

• Neuronal morphology is specialized for directional electrical signaling rather than existing as uniform, spherical cells:

  • Dendrites: Branched processes specialized to receive chemical and electrical inputs from upstream synaptic connections.

  • Soma: The metabolic cell body housing the nucleus; serves as the integrative hub summing graded postsynaptic potentials.

  • Axon: A specialized cylindrical extension designed to propagate electrical impulses rapidly across long distances to downstream targets.

• Passive membrane properties govern subthreshold electrical signaling in biological membranes:

  • When subthreshold electrical currents are injected into an axon, the resulting membrane potential change decays exponentially over space.

  • The signal attenuates over time due to membrane resistance ($R_m$) and membrane capacitance ($C_m$).

  • Because passive electrical spread diminishes rapidly across physical distance, passive conduction alone cannot transmit signals across long axonal tracts.

  • Neurons actively boost and regenerate signals over long distances through the generation of action potentials.

• Electrophysiological recording conventions dictate the graphic interpretation of currents and voltages:

  • Membrane potential ($V_m$): The difference in electrical charge across the plasma membrane, defined as intracellular potential minus extracellular potential ($V_m = V_{\text{inside}} - V_{\text{outside}}$).

  • Units of measurement: Electrical current ($I$) is measured in amperes ($\text{A}$, typically recorded as picoamperes, $\text{pA}$, or nanoamperes, $\text{nA}$); voltage is measured in volts ($\text{V}$, typically millivolts, $\text{mV}$).

  • Inward current: Depicted as a downward deflection on electrophysiological recording axes; represents either the influx of positive ions into the cell or the efflux of negative ions out of the cell. Inward current causes membrane depolarization.

  • Outward current: Depicted as an upward deflection; represents either the efflux of positive ions out of the cell or the influx of negative ions into the cell. Outward current causes membrane hyperpolarization.

The Electrochemical Driving Force & The Neuronal Number Line

• The electrochemical driving force represents the net physical force acting on a permeant ion across a cell membrane:

  • Formula: $\text{Driving force} = V_m - E_{\text{ion}}$

  • $V_m$ is the instantaneous membrane potential, and $E_{\text{ion}}$ is the equilibrium potential of that specific ion.

  • The driving force quantitatively reflects the difference between the actual membrane potential and the potential at which the ion would be in dynamic equilibrium.

• Physical interpretation of driving force values:

  • When $V_m = E_{\text{ion}}$, the driving force equals $0\,\text{mV}$. Under this condition, there is no net movement of the ion, and net current is zero even if the membrane is completely permeable to that ion.

  • Because the direction of current flips as $V_m$ moves from values greater than $E_{\text{ion}}$ to values less than $E_{\text{ion}}$, an ion's equilibrium potential is functionally referred to as its reversal potential.

• Application of Ohm's law to individual ionic currents:

  • General physical law: $I = V \times G$, where $I$ is current, $V$ is voltage, and $G$ is electrical conductance.

  • Formulation for a specific ion: $I_{\text{ion}} = (V_m - E_{\text{ion}}) \times g_{\text{ion}}$

  • The term $g_{\text{ion}}$ (lowercase $g$) denotes the membrane conductance specific to that ion or channel population.

  • If channels are closed ($g_{\text{ion}} = 0\,\text{S}$), no current flows regardless of driving force magnitude.

  • If channels are open ($g_{\text{ion}} > 0\,\text{S}$), current magnitude depends directly on the magnitude of the driving force ($V_m - E_{\text{ion}}$).

• Quantitative case studies of ionic driving forces:

  • Sodium ($\text{Na}^+$):

  • Extracellular concentration $[\text{Na}^+]_o = 150\,\text{mM}$; intracellular concentration $[\text{Na}^+]_i = 15\,\text{mM}$.

  • Equilibrium potential: $E_{\text{Na}} = \frac{60}{+1} \log_{10}\left(\frac{150}{15}\right) = +60\,\text{mV}$.

  • At $V_m = +60\,\text{mV}$, the driving force is $+60\,\text{mV} - (+60\,\text{mV}) = 0\,\text{mV}$.

  • At $V_m = +30\,\text{mV}$, the driving force is $+30\,\text{mV} - (+60\,\text{mV}) = -30\,\text{mV}$. The positive ion experiences a $-30\,\text{mV}$ equivalent attractive force toward the cell interior, driving an inward current that depolarizes $V_m$.

  • Potassium ($\text{K}^+$):

  • Extracellular concentration $[\text{K}^+]_o = 4\,\text{mM}$; intracellular concentration $[\text{K}^+]_i = 120\,\text{mM}$.

  • Equilibrium potential: $E_{\text{K}} = \frac{60}{+1} \log_{10}\left(\frac{4}{120}\right) = -88.7\,\text{mV}$.

  • At a resting potential of $V_m = -60\,\text{mV}$, the driving force is $-60\,\text{mV} - (-88.7\,\text{mV}) = +28.7\,\text{mV} \approx +29\,\text{mV}$. The positive ion experiences a $+29\,\text{mV}$ repulsive drive pushing it out of the cell, driving an outward current.

  • Chloride ($\text{Cl}^-$):

  • Given $[\text{Cl}^-]_o = 100\,\text{mM}$ and $[\text{Cl}^-]_i = 10\,\text{mM}$, $E_{\text{Cl}} = -60\,\text{mV}$.

  • At a hyperpolarized potential of $V_m = -75\,\text{mV}$, the driving force is $-75\,\text{mV} - (-60\,\text{mV}) = -15\,\text{mV}$.

  • Because chloride carries a negative charge ($z = -1$), an interior potential more negative than $E_{\text{Cl}}$ repels $\text{Cl}^-$ outward. The outward movement of negative charge constitutes an inward electrical current, depolarizing the membrane toward $-60\,\text{mV}$.

• Standard physiological equilibrium potentials and driving forces at resting membrane potential ($V_{\text{rest}} = -70\,\text{mV}$):

  • $E_{\text{K}} = -90\,\text{mV}$

  • $E_{\text{Cl}} = -60\,\text{mV}$

  • $V_{\text{rest}} = -70\,\text{mV}$

  • $E_{\text{Na}} = +60\,\text{mV}$

  • $E_{\text{Ca}} = +120\,\text{mV}$

  • Potassium driving force: $-70\,\text{mV} - (-90\,\text{mV}) = +20\,\text{mV}$. Cations are repelled outward; physical outward movement represents an outward, hyperpolarizing current.

  • Chloride driving force: $-70\,\text{mV} - (-60\,\text{mV}) = -10\,\text{mV}$. Anions are repelled outward; physical outward movement of negative charge represents an inward, depolarizing current.

  • Sodium driving force: $-70\,\text{mV} - (+60\,\text{mV}) = -130\,\text{mV}$. Cations are pulled inward; physical inward movement represents an inward, depolarizing current.

  • Calcium driving force: $-70\,\text{mV} - (+120\,\text{mV}) = -190\,\text{mV}$. Divalent cations ($z = +2$) are pulled inward; physical inward movement represents an inward, depolarizing current.

• Systematic approaches to determine ionic flow:

  • Method 1 (Equilibrium Target): Compare $V_m$ directly to $E_{\text{ion}}$. Increasing permeability to any ion always moves $V_m$ toward that ion's $E_{\text{ion}}$. Depolarization requires inward current; hyperpolarization requires outward current. Next, apply the ion's charge to convert current direction into physical ion movement (e.g., inward current corresponds to cation influx or anion efflux).

  • Method 2 (Vector Arithmetic): Calculate the mathematical sign of $V_m - E_{\text{ion}}$. Match the sign against the ion's charge to determine physical repulsion or attraction across the lipid bilayer.

The Resting Membrane Potential & The Goldman-Hodgkin-Katz Equation

• The fundamental determinant of membrane potential:

  • When a membrane becomes permeable to an ion, that ion flows down its electrochemical gradient, pulling $V_m$ toward its own equilibrium potential ($E_{\text{ion}}$), regardless of the initial membrane potential.

  • In multi-ion systems, $V_m$ reflects a tug-of-war where each permeant ion exerts a pull toward its $E_{\text{ion}}$ weighted directly by its relative membrane permeability.

• Membrane potential as a localized capacitive phenomenon:

  • The electrical potential difference ($V_m$) is established across the lipid bilayer by an ultra-thin layer of separated charge resting directly on the inner and outer membrane surfaces.

  • The actual physical quantity of ions crossing the membrane to change $V_m$ represents an infinitesimally small fraction of the total ionic content within the cytoplasm.

  • Macroscopic intracellular and extracellular bulk ion concentrations remain constant during signaling events, meaning that signaling-associated shifts in $V_m$ do not alter bulk concentration gradients or change $E_{\text{ion}}$.

• The Goldman-Hodgkin-Katz (GHK) voltage equation:

  • Used to calculate the steady-state membrane potential in a multi-ion system:

$V_m = \frac{RT}{F} \ln\left( \frac{p_{\text{K}}[\text{K}^+]_o + p_{\text{Na}}[\text{Na}^+]_o + p_{\text{Cl}}[\text{Cl}^-]_i}{p_{\text{K}}[\text{K}^+]_i + p_{\text{Na}}[\text{Na}^+]_i + p_{\text{Cl}}[\text{Cl}^-]_o} \right)$

• $R$ is the ideal gas constant, $T$ is absolute temperature in Kelvin, and $F$ is the Faraday constant.

• The concentrations for chloride are inverted ($[\text{Cl}^-]_i$ in the numerator, $[\text{Cl}^-]_o$ in the denominator) because chloride's negative valence ($z = -1$) mathematically reverses its logarithmic concentration ratio relative to monovalent cations.

• If the membrane is selectively permeable to only a single ion, all other permeability coefficients drop to zero, reducing the GHK equation directly to the Nernst equation for that specific ion.

  • Distinguishing permeability and conductance:

• Permeability ($p_{\text{ion}}$) reflects the intrinsic ease with which an ion diffuses across the membrane; it is unitless and typically normalized as a relative ratio.

• Conductance ($g_{\text{ion}}$) represents the actual electrical current-carrying capability of the membrane for an ion; it is measured in Siemens ($\text{S} = 1 / \Omega$).

• Resting permeability hierarchy: $p_{\text{K}} > p_{\text{Cl}} > p_{\text{Na}} > p_{\text{Ca}}$.

• Standard relative baseline ratios at rest: $p_{\text{K}} = 1$, $p_{\text{Cl}} = 0.45$, $p_{\text{Na}} = 0.05$.

• Physical basis of resting permeability:

  • Resting membrane permeability is mediated by constitutively active potassium leak channels.

  • These transmembrane leak channels are not gated by voltage and remain open at resting membrane potentials.

  • Decreased genetic or protein expression of potassium leak channels reduces resting $p_{\text{K}}$, decreasing the hyperpolarizing influence of potassium and driving $V_{\text{rest}}$ more positive (depolarization). However, changing leak channel expression has zero effect on concentration gradients, leaving $E_{\text{K}}$ unchanged.

• Numerical modeling of resting potential parameters:

  • Baseline parameters: $T = 310\,\text{K}$, $p_{\text{K}} = 1$, $p_{\text{Na}} = 0.05$, $p_{\text{Cl}} = 0.45$, $[\text{K}^+]_o = 4\,\text{mM}$, $[\text{K}^+]_i = 120\,\text{mM}$, $[\text{Na}^+]_o = 150\,\text{mM}$, $[\text{Na}^+]_i = 15\,\text{mM}$, $[\text{Cl}^-]_o = 120\,\text{mM}$, and $[\text{Cl}^-]_i = 5\,\text{mM}$.

  • Calculated baseline resting membrane potential: $V_m = -67.91\,\text{mV}$.

  • Effects of altering concentrations:

  • Doubling extracellular potassium ($[\text{K}^+]_o$ from $4\,\text{mM}$ to $8\,\text{mM}$) causes marked depolarization because potassium possesses the highest resting permeability ($p_{\text{K}} = 1$).

  • Changing $[\text{Na}^+]$ or $[\text{Cl}^-]$ produces significantly smaller shifts in $V_m$ because their relative permeabilities are much lower at rest ($0.05$ and $0.45$, respectively).

  • Completely swapping the internal and external concentration gradients of $\text{K}^+$ produces a massive voltage swing compared to swapping the $\text{Na}^+$ gradient.

  • Effects of altering permeabilities:

  • Setting $p_{\text{K}} = 0$ removes potassium's pull, allowing chloride and sodium to dominate and depolarizing $V_m$.

  • Modifying the permeability to a given ion shifts $V_m$ toward or away from that ion's $E_{\text{ion}}$, but has zero impact on the $E_{\text{ion}}$ values of any of the ions.

  • Shifting $V_m$ via permeability changes subsequently alters the electrochemical driving force ($V_m - E_{\text{ion}}$) experienced by every ion species in the system.

• Pathophysiological disruption of chloride homeostasis in Spinal Cord Injury (SCI):

  • Intracellular chloride concentration is dynamically regulated by two primary active cotransporters:

  • KCC2: Potassium-chloride cotransporter 2; functions as a chloride exporter, driving $\text{Cl}^-$ out to maintain low intracellular chloride.

  • NKCC1: Sodium-potassium-chloride cotransporter 1; functions as a chloride importer, transporting $\text{Cl}^-$ into the cell.

  • Intact physiological baseline: High KCC2 expression maintains a steep outward chloride gradient ($[\text{Cl}^-]_o / [\text{Cl}^-]_i = 10$), establishing $E_{\text{Cl}} = -60\,\text{mV}$. Under these conditions, opening chloride channels causes hyperpolarization or shunting inhibition.

  • Following spinal cord injury (SCI-7d and SCI-28d):

  • KCC2 protein expression is significantly downregulated.

  • NKCC1 protein expression is significantly upregulated.

  • Intracellular chloride accumulates, collapsing the ratio to $[\text{Cl}^-]_o / [\text{Cl}^-]_i = 2$, which shifts $E_{\text{Cl}}$ from $-60\,\text{mV}$ up to $-18\,\text{mV}$.

  • With $E_{\text{Cl}}$ shifted above resting potential ($-70\,\text{mV}$), opening ligand-gated chloride channels (such as GABA and glycine receptors) causes an anomalous efflux of chloride, depolarizing the neuron and contributing to neuropathic pain and spasticity.

  • Rehabilitation via exercise training (SCI-28d+Ex) counteracts these molecular changes, restoring KCC2 and NKCC1 protein ratios toward intact baseline levels.

Voltage-Gated Sodium Channel Biophysics & Single-Channel Properties

• Structural topology of voltage-gated sodium channels (VGSCs / Nav):

  • Nav channels comprise a primary pseudotetrameric pore-forming alpha subunit consisting of four homologous domains (I, II, III, and IV).

  • Each homologous domain spans the membrane six times via alpha-helices labeled S1 through S6.

• Voltage-Sensing Domain (VSD): Formed by segments S1 through S4 in each domain. Segment S4 contains positively charged arginine and lysine residues positioned every third amino acid. Depolarization exerts electrostatic repulsion on S4, driving it outward through the membrane to trigger pore opening.

• Selectivity Filter and Pore: Segments S5 and S6, along with the intervening re-entrant pore loop (P-loop), form the central conduction pore and the narrow selectivity filter (constituted by the DEKA motif: Asp, Glu, Lys, Ala).

• Electrophysiological analysis via patch clamp recordings:

  • Single-channel patch clamp isolates microscopic currents flowing through an individual Nav channel during a depolarizing voltage step ($V_p$).

  • Individual sodium channels open stochastically with brief open durations, each producing an inward current pulse of approximately $5\,\text{pA}$.

  • Individual channels open early in response to depolarization and rapidly inactivate.

  • Summing or averaging hundreds of individual recording sweeps yields the macroscopic inward current profile: a rapid transient inward current with a smooth average amplitude of approximately $0.2\,\text{pA}$.

• The structural mechanism of channel inactivation:

  • Rapid inactivation operates via a ball-and-chain (hinged-lid) mechanism mediated by an intracellular peptide loop connecting domains III and IV.

  • The hydrophobic IFM motif (isoleucine-phenylalanine-methionine) acts as a physical plug that binds the cytoplasmic mouth of the pore shortly after activation.

  • Functional evidence from the Drosophila Shaker potassium channel ($\text{ShB}$):

  • Wild-type $\text{ShB}$ channels activate and immediately inactivate during sustained depolarization steps to $+50\,\text{mV}$.

  • Deletion of the intracellular amino-terminal inactivation domain (residues 6 through 46, designated $\text{ShB}\Delta 6\text{--}46$) completely eliminates inactivation, yielding a channel that remains continuously open for the duration of the depolarizing step.

• The three operational conformational states of voltage-gated sodium channels:

  • 1. Closed state: Channel is deactivated but fully primed to open; predominates at resting or hyperpolarized potentials ($\le -60\,\text{mV}$).

  • 2. Open state: Membrane depolarization above threshold (around $-50\,\text{mV}$ to $-30\,\text{mV}$) triggers S4 outward movement, opening the activation gate to permit $\text{Na}^+$ influx.

  • 3. Inactivated state: The inactivation loop swings into the open pore around $0\,\text{mV}$, blocking ionic flux. The channel cannot reopen directly from this state.

  • De-inactivation: In order to exit the inactivated state, the membrane must repolarize to hyperpolarized resting levels ($\le -60\,\text{mV}$), allowing the inactivation plug to dislodge and the activation gates to reset to the closed state.

Action Potential Generation, Phases, and Threshold Dynamics

• Transformation of graded inputs into binary signaling:

  • Graded inputs: Subthreshold membrane potential fluctuations that vary continuously in amplitude, duration, and polarity based on stimulus intensity.

  • Action potential: An active, all-or-none, binary electrical signal. Once elicited, all action potentials generated by a given neuron have identical amplitude and waveform.

• Action potential threshold ($V_{\text{threshold}}$):

  • The critical voltage to which a neuronal membrane must be depolarized to trigger an action potential (typically between $-55\,\text{mV}$ and $-50\,\text{mV}$).

  • Threshold is the exact tipping point where the inward sodium current ($I_{\text{Na}}$) exceeds the combined outward currents mediated by potassium leak channels and chloride fluxes.

  • Passing threshold initiates the Hodgkin cycle: Depolarization opens voltage-gated $\text{Na}^+$ channels $\rightarrow$ inward $\text{Na}^+$ current increases $\rightarrow$ membrane depolarizes further $\rightarrow$ additional Nav channels open in an explosive positive feedback cascade.

• Biological case study: Zebrafish Mauthner neuron escape circuit (Marsden & Granato, 2015):

  • The paired giant Mauthner neurons in the zebrafish hindbrain receive acoustic inputs from the ear and drive the ultrafast C-start escape response.

  • In vivo optical calcium imaging ($\Delta F / F_0$ proxy for depolarization and calcium influx) evaluates subthreshold versus thresholded signaling across acoustic stimuli: $-24\,\text{dB}$, $-18\,\text{dB}$, $-15\,\text{dB}$, $-12\,\text{dB}$, $-7\,\text{dB}$, and $+13\,\text{dB}$ (startle threshold).

  • Lateral dendrite: Exhibits continuous, graded calcium responses that scale proportionally with sound intensity, failing to show all-or-none behavior.

  • Soma and axon initial segment: Maintain zero response during subthreshold auditory inputs ($-24\,\text{dB}$ to $-7\,\text{dB}$), but switch abruptly to an explosive, maximal calcium transient exclusively when the stimulus reaches startle threshold ($+13\,\text{dB}$).

  • This compartmentalization reflects dense localization of voltage-gated sodium channels at the axon initial segment and soma, which convert graded dendritic sensory inputs into binary escape behaviors.

• The distinct kinetic phases of the neuronal action potential:

  • 1. Rising phase (Depolarization): Depolarization past $V_{\text{threshold}}$ rapidly opens Nav channels, driving sodium conductance ($g_{\text{Na}}$) skyward. Massive inward sodium current pushes $V_m$ upward toward $E_{\text{Na}} (+60\,\text{mV})$.

  • 2. Peak / Overshoot: $V_m$ reverses polarity, reaching a peak typically between $+30\,\text{mV}$ and $+40\,\text{mV}$.

  • 3. Falling phase (Repolarization): Rapid decline in $V_m$ caused by two concurrent events:

  • Voltage-dependent inactivation of Nav channels shuts off inward sodium current ($I_{\text{Na}}$).

  • Delayed opening of voltage-gated potassium channels (Kv) allows outward potassium current ($I_{\text{K}}$) to flow down its electrochemical gradient.

  • 4. Afterhyperpolarization (AHP / Undershoot): Kv channels deactivate with a time lag, leaving the membrane with an elevated potassium permeability ($p_{\text{K}}$) that exceeds resting levels. This temporarily pulls $V_m$ down toward $E_{\text{K}} (-90\,\text{mV}$, significantly more negative than normal $V_{\text{rest}}$).

  • 5. Recovery: Kv channels close, Nav channels de-inactivate, and background leak conductances restore $V_m$ to resting potential ($-70\,\text{mV}$).

Voltage-Gated Potassium Channels & Repolarization Mechanics

• Comparative molecular architecture of Nav versus Kv channels:

  • Nav channels consist of a single continuous polypeptide chain containing four linked homologous repeats (I-IV), each with segments S1-S6.

  • Kv channels are true tetrameric protein complexes assembled from four distinct polypeptide subunits, each containing six transmembrane segments (S1-S6) that co-assemble symmetrically around a central ion pore.

• Conductance kinetics and operational profiles:

  • Voltage-gated sodium channels: Exhibit ultrafast activation kinetics and rapid, autonomous inactivation within $1\text{--}2\,\text{ms}$.

  • Voltage-gated potassium channels (delayed rectifiers):

  • Open with a delayed time course relative to sodium channels in response to depolarization.

  • Inactivate extremely slowly, if at all, during the physiological duration of an action potential.

  • The temporal difference in channel kinetics is necessary for signal generation: if Kv channels activated as rapidly as Nav channels, simultaneous outward $\text{K}^+$ current would counteract inward $\text{Na}^+$ current, preventing the membrane from reaching threshold.

• Genetic and functional analysis of Kv mutants (Kv1.1 wild type vs. L296F):

  • Electrophysiological recordings examine currents elicited by stepping voltage from a holding potential of $-120\,\text{mV}$ to test potentials between $-100\,\text{mV}$ and $+60\,\text{mV}$ in $10\,\text{mV}$ increments.

  • Wild-type Kv1.1: Generates sustained, non-inactivating outward currents throughout the entire duration of the depolarizing voltage pulse.

  • L296F mutant: The leucine-to-phenylalanine substitution alters channel gating kinetics, inducing premature channel inactivation and current decay that shortens outward potassium flow.

• Clear distinction between leak and voltage-gated potassium conductances:

  • Potassium leak channels: Non-voltage-sensitive; remain constitutively open at resting potential; establish $V_{\text{rest}}$.

  • Voltage-gated potassium channels (delayed rectifiers): Voltage-sensitive; strictly closed at normal resting potential; activate only when the cell depolarizes, driving repolarization and the AHP.

Refractory Periods, Axonal Propagation, and Saltatory Conduction

• The physical basis of refractory periods:

  • Absolute refractory period: The time interval immediately following the action potential peak during which it is physically impossible to trigger a second action potential, regardless of stimulus strength. This occurs because the vast majority of Nav channels reside in the inactivated state, with their inactivation loops blocking the pore.

  • Relative refractory period: The subsequent time window during which a second action potential can be triggered, but requires a much stronger depolarizing current than baseline. During this period, some Nav channels have de-inactivated into the closed-competent state, but residual Kv channels remain open, producing elevated outward conductance ($g_{\text{K}}$) and afterhyperpolarization that actively opposes depolarizing inputs.

• Mechanisms of active action potential propagation:

  • Longitudinal local current loops: Inward sodium current flowing through open Nav channels at the active zone accumulates on the inner membrane surface. This positive charge flows down the axial resistance of the intracellular cytoplasm toward adjacent downstream regions.

  • Depolarization of adjacent patches: As positive charge spreads internally, it depolarizes the adjacent, resting downstream membrane patch toward $V_{\text{threshold}}$.

  • Downstream regenerative activation: Reaching threshold opens local Nav channels in the adjacent patch, generating an action potential anew.

  • Unidirectional propagation: The action potential cannot reverse direction and travel backward because the upstream membrane patch it just excited is in its absolute refractory period, with its Nav channels fully inactivated.

• Structural and biophysical properties of the myelin sheath:

  • Myelin is a thick, lipid-rich membrane sheath produced by glial cells (oligodendrocytes in the central nervous system; Schwann cells in the peripheral nervous system) that wraps concentrically around axonal segments.

  • Biophysical impact: Myelin increases membrane resistance ($R_m$) by reducing ionic leak through the membrane to near zero, while simultaneously decreasing membrane capacitance ($C_m$).

  • Because current cannot leak across the internodal membrane, passive longitudinal current spread travels significantly faster and over much greater distances without degrading below threshold.

• Saltatory conduction and the Nodes of Ranvier:

  • Nodes of Ranvier: Unmyelinated periodic gaps along the axon spaced $200\,\mu\text{m}$ to $2\,\text{mm}$ apart.

  • Nodes express an exceptionally high density of voltage-gated sodium channels and potassium channels.

  • Mechanism of saltatory conduction: Active inward sodium currents are generated exclusively at the nodes of Ranvier. The current then sweeps passively, electrotonically, and rapidly through the insulated internodal segment, arriving at the next node to trigger another action potential. This makes conduction appear to jump from node to node.

  • Saltatory conduction drastically accelerates conduction velocity while minimizing metabolic energy expenditure (reducing the quantity of ATP required by the $\text{Na}^+/\text{K}^+$ ATPase pump to restore ion gradients).

• Clinical pathology: Multiple Sclerosis (MS):

  • Multiple sclerosis is an autoimmune neuroinflammatory disease in which autoreactive immune cells target and degrade the myelin sheath of central nervous system axons.

  • Demyelination exposes uninsulated axon segments that lack sufficient densities of voltage-gated sodium channels.

  • Exposed internodes leak outward current, causing propagating signals to dissipate below threshold before reaching the next node of Ranvier, leading to conduction slowdown, conduction block, and severe neurological deficits.