NEUR30080 L3 SQ action potential

learning objectives

the waveform: one spike, five phases

1. rest (-65 mV): K+ leak channels dominate, holding Vm near Ek

2. threshold (-55 mV): the point where the feedback runs away

3. upstroke and overshoot (+30 mV): Na+ enters in and briefly flips the polarity

4. repolarisation: Na+ channels inactivate and K+ efflux pulls Vm back down

5. after-hyperpolarisation (-80 mV): K+ channels close late, so Vm dips past rest

waveform image

all-or-nothing

• sub-threshold input: elicits only passive electrotonic decay (the Lecture 2 membrane)

• supra-threshold input: triggers an identical, full-amplitude AP regardless of stimulus excess

• amplitude is uninformative: fixed size of the spike means individual APs carry no graded information

• rate coding: stimulus intensity is encoded entirely by spike frequency (Hz), never by amplitude

this is why a pinprick and a hammer blow produce the same size of AP, and very different firing rates

all-or-nothing image

recording the spike two ways

• intracellular recording: the electrode penetrates the cell, directly measuring the full 100 mV transmembrane voltage (Vm)

• extracellular recording: an external electrode detects minute local current sinks and sources in the EC fluid

• signal attenuation: the recorded wavelength is tiny (100 uV), biphasic

• non-destructive: allows for stable, LT in vivo recording without compromising the cell memb

one channel, two gates

• activation gate:

  • closed at rest

  • opens rapidly upon depol via the S4 voltage sensor

• inactivation gate:

  • open at rest

  • closes slowly upon depol

  • steric occlusion via a tethered ‘ball-and-chain’ mechanism

closed different to inactivated

inactivation and activation gates: kinetic disparity

both gates respond to depolarisation, but kinetic delay between activation and inactivation creates the transient Na+ current

inactivation and activation gates: voltage-dependent reset

repolarisation is an absolute requirement to dislodge the inactivation gate

threshold is where the feedback runs away

• The Hodgkin Cycle: Initial depolarisation opens Nav channels → Na+ influx → further depolarisation → more Nav open

• Positive Feedback: This self-amplifying loop rapidly drives the membrane toward ENa

• Sub-threshold Damping: Below threshold, K+ efflux exceeds Na+ influx, damping the cycle and restoring the resting potential

• Threshold Crossing: The critical voltage where inward Na+ current irreversibly exceeds outward K+ current

threshold is not s fixed channel property, it is the precise voltage where inward Na+ current irreversibly exceeds outward K+ current

why the peak stops short

• The Thermodynamic Limit: ENa is +58 mV, but the peak arrests at ~+30 mV.

• Nav Inactivation: The slow inactivation gate sterically occludes the pore, terminating Na+ influx

• Delayed Rectifier Activation: Voltage-gated K+ channels (Kv) finally open, introducing a massive outward K+ current

• Continuous Leak: Resting K+ leak channels continuously oppose depolarisation

the AP is a kinetic race between an inward current that inactivates early and an outward current that activates late

repolarisation and the undershoot

• Dual Mechanism Repolarisation: Nav inactivation removes inward current, while Kv activation provides strong outward current

• Kinetic Delay (Kv): Delayed rectifier channels open late, allowing the initial rapid upstroke.

• Prolonged gK: Kv channels are slow to deactivate, maintaining high K+ permeability as Vm drops

• The Undershoot (AHP): Elevated PK transiently drives Vm closer to EK (~ −80 mV) than at rest

the undershoot is not a separate mechanism, it is just the K+ channels being late to leave

phases of the spike table

refractory periods due to inactivation

• absolute refractory

• relative refractory

• frequency cap

• complete reset

absolute refractory period

• infinite threshold

• Nav channels are physically inactivated (sterically occluded)

a channel state, not a shortage of ions

relative refractory period

• elevated threshold

• a subset of Nav channels have reset, but residual gk strongly opposes depolarisation

frequency cap

together, the refractory periods restrict maximum firing rates to a few 100 Hz

complete reset

• once fully repolarised, the channels fully reset

• gradients are functionally unconsumed

refractory periods due to inactivation image

research using giant squid axon

• Hodgkin and Huxley (1952): Utilised the squid giant axon and voltage clamp technique

• Mathematical Inference: Separated ionic currents and mathematically predicted the kinetic behaviour of distinct 'gates

• Predictive Power: The model accurately predicted gating charge movements, physically verified decades later

• Predictive Power: The model accurately predicted gating charge movements, physically verified decades late

Q:

the trigger zone

• the axon hillock segment

• a highly specialised 20-60 um unmyelinated domain directly proximal to the soma

• Ankyrin-G and betaIV-spectrin physically anchor the channels into this high-density matrix

• low threshold Nav1.6 is clustered distally (where the spike initiates), while Nav1.2 sits proximally

ankyrin-G significance

lose ankyrin-G and the axon will grow spines and start behaving like a dendrite

the axon initial segment (AIS) defines neuronal polarity

channels are localised

• Nav clustering: strictly localised to the AIS and the Nodes of Ranvier - the exclusive sites of active regeneration

• Kv1 localisation: sequestered at juxtaparanodes beneath the myelin to damp pathological repetitive firing

• Kv7 (M-current): positioned at the AIS and nodes to regulate threshold dynamics and resting excitability

• structural plasticity: the AIS is dynamic, chronic depol physically shifts the structure distally to reduce excitability

channels are localised image

a neuron does not have one uniform excitability

different subcellular patches express completely discrete channel populations

mechanism of spread: local circuits

• the actively firing membrane patch acts as a massive current source due to local Na+ influx

• electrotonic spread: current spreads passively down the axon, dictated entirely by the length constant (lambda)

• the advancing passive depol triggers durther depol in the adjacent memb patch

• nothing physically ‘travels’, each discrete patch ignites the next, analogous to a burning fuse

passive electrotonic spread drives current forward and active regeneration restores the amplitude

both essential for long-distance propagation

mechanism of spread image

direction

• only goes forwards because intracellular current spreads bidirectionally

• the immediately preceding membrane patch is in its absolute refractory period (Nav channels inactivated)

• consequently, only the ‘resting’ membrane ahead can successfully depolarise

• stimulate mid-axon: initiates bidirectional propagation (orthodromic and antidromic) because both adjacent patches are resting

direction enforced by refractoriness, not by structure

direction image

conduction velocity

increasing diameter of axons

myelin: optimises by changing both constants at once

• maximising lambda: multiple lipid layers in series massively increase transmemb resistance (Rm), essentially eliminating passive leak

• minimising tau: increasing the dielectric thickness drastically reduces total membrane capacitance (Cm), allowing near-instantaneous charging

• lambda and tau up and down together: myelin successfully optimises both biophysical constraints simultaneously

• internodes about 100x the axon diameter

myelinated axon image

oligodendrocytes

myelinate many axons each in the CNS

schwann cells

make exactly one internode each in the PNS

Nodes of Ranvier

• one bare membrane, every 2 mm

• Nodes of Ranvier (1 um) contain the highest Nav channel density in the nervous system.

• Under the myelin, the signal spreads purely via fast, passive electrotonic decay. Nothing physically 'jumps'

• At the node, the arriving passive voltage triggers the depolarisation, rebuilding a fresh action potential from scratch

• The Safety Factor (~3-5x): The passive current arriving at a node is safely several times larger than the required threshold current

saltatory conduction misnomer

• implies leaping, but this is misnomer

• the signal is passively carried and actively rebuilt

demyelination

• the safety factor falls below one

• Demyelination causes Rm to plummet and Cm to spike; lambda shortens catastrophically while tau lengthens

• Passive current decays completely before reaching the next node

• Conduction Block: The safety factor drops below 1.0, causing the propagating signal to permanently stall and die

• Increased temperature accelerates channel kinetics, prematurely terminating Nav influx and further reducing the safety factor

demyelination image

Uthoff’s phenomenon

MS symptoms worsen with a hot bath, exercise or fever

how you take the spike apart table

Q:

learning outcomes