1. Action Potential

When stimulation reaches threshold potential, an Action Potential is initiated, triggering a travelling of electric wave of APs of constant amplitude

• Threshold for Initiation: as depolarising current increases, $V_m \to -50mV$
• All or Nothing Event: AP stereotyped regardless of amount past threshold
• Self-regenerative: can be conducted over great distances
• Refractory Period: limits frequency of signals

2. Voltage Clamp Experiment

Measure Current contributing to an Action Potential

An Recording Electrode is placed inside the cell and electronically compares this Membrane Potential with the Command Potential

The clamp circuitry passes a current back into the cell through Current-passing Electrode, the feedback circuit holds the Membrane Potential at the desired level

Small Command Voltage(A) - A passive current change is observed

Large Command Voltage(B) - A large initial outward current peak, $I_c$, is followed by a large inward current that turns later into a pertaining outward current.

By applying pharmacological drugs during Action Potential the current waveform could be analyised in more detail:

TTX - Tetrodotoxin, a blocker of $Na^+$ Channel

reveals the contribution of $K^+$ current, $I_K$

TEA - Tetraethyl-ammonium, a blocker of $K^+$ Channel

reveals the contribution of $Na^+$ current, $I_{Na}$

<aside> 💡 During an Action Potential, the current-voltage relationship becomes non-linear

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$I_m$ - Induction of a current by the voltage clamp to achieve the command voltage

$I_{Na}$ - A fast inward current through the variable conductance, $g_{Na}$

$I_K$ - Slightly delayed outward current through the variable conductance, $g_K$

$I_l$ - Leakage current through the constant conductance, $g_l$, representing the conductance of all of the resting non-gated channel

$$ I_K = g_K(V_m-E_K)\\ g_K = \frac{I_K}{V_m - E_K} $$

$$ I_{Na} = g_{Na}(V_m-E_{Na})\\ g_{Na} = \frac{I_{Na}}{V_m - E_{Na}} $$

3. Voltage-gated $Na^+$ Channels

Closed Activable

At Resting Membrane Potential, the $Na^+$ Channels are closed

Open

Once the membrane capacity is discharged, and the membrane potential is depolarised to a certain degree, the Activation Gate opens which initiates the $Na^+$ influx

This further depolarises the membrane and opens even more voltage-gated $Na^+$ Channels (Positive Feedback)

Closed Inactivable

After a short period of time, the channel automatically closes by means of a slow Inactivation Gate

The Inactivation Gate is only removed and replaced with Activation Gate if the membrane potential drops to negative Resting Potential levels or below

Depolarisation

Massive influx of $Na^+$, fast inward current, during Action Potential drives the membrane potential towards the $Na^+$ equilibrium potential, $E_{Na}$

Repolarisation

Delayed efflux of $K^+$, delayed outward current, polarises the membrane towards the $K^+$ equilibrium potential, $E_K$

Essential for the transition of voltage-gated channels from the Closed Inactivatble state to Closed Activable state, which is necessary condition for the neuron being able to generate another action potential

Overview

Depolarisation of the membrane beyond threshold (~ − 50mV) occurs

• $\uparrow g_{Na}$ as $Na^+$-VGCs open rapidly
• Inward $Na^+$ current

Membrane capacitance discharged causing further depolarisation

• Positive feedback causes more $Na^+$-VGCs to open
• Increase in inward $Na^+$ current
• Regenerative process drives $V_m\to E_{Na}$
• This is the rising phase of the AP

$Na^+$-VGCs gradually inactivated and $K^+$-VGCs open with some delay (delayed rectifier)

• $\downarrow g_{Na}$ and $\uparrow g_{K}$
• Outward $K^+$ current tends to repolarise the membrane

Hyperpolarisation occurs

• $V_m$ depolarises past resting potential
  • $K^+$-VGCs take time to close so $g_{K} > g_{K\,\mathrm{resting}}$ for a few ms
  • $V_m$ is closer to $E_K$
• This is the absolute refractory period
• As some $K^+$ channels close and $Na^+$ channels recover from inactivation the relative refractory period is entered

4. Patch Clamp Experiment

5. Propagation of Action Potential along Axon

6. Synapses - Signal Transmission between Neurons

Electrical Synapse