Action Potential Dynamics, Axonal Propagation, and Synaptic Transmission

Membrane Potential Dynamics and the Action Potential Cycle

Resting Membrane Potential (RMP):
- The baseline electrical charge across the plasma membrane of an excitable cell at rest is $-70\,\text{mV}$ .
- Maintained by unequal distribution of ions across the membrane and continuous background transport.
Threshold Potential:
- The critical voltage level required to initiate an all-or-none action potential is $-55\,\text{mV}$ .
- A stimulus must depolarize the membrane from $-70\,\text{mV}$ up to $-55\,\text{mV}$ to trigger the opening of voltage-gated ion channels.
Phases of the Action Potential:
- Depolarization:
  - Triggered when an incoming stimulus brings the membrane potential to threshold ( $-55\,\text{mV}$ ).
  - Voltage-gated sodium ( $\text{Na}^+$ ) channels open, resulting in rapid $\text{Na}^+$ entry ( $\text{Na}^+:\text{in}$ ) into the intracellular fluid along its electrochemical gradient.
  - The entry of positive charge drives the membrane potential upward past $0\,\text{mV}$ , peaking at approximately $+30\,\text{mV}$ .
  - This phase constitutes a complete reversal of membrane polarization (from a negative interior to a positive interior).
- Repolarization:
  - At the peak ( $+30\,\text{mV}$ ), voltage-gated $\text{Na}^+$ channels inactivate, and voltage-gated potassium ( $\text{K}^+$ ) channels open.
  - Potassium ions exit the cell ( $\text{K}^+:\text{out}$ ) down their electrochemical gradient.
  - The loss of positive ions drives the membrane potential back downward toward negative values ("repolarization: more negative").
- After-Hyperpolarization (Hyperpolarizing Phase):
  - Voltage-gated $\text{K}^+$ channels remain open briefly after reaching resting levels, allowing continued potassium efflux.
  - The membrane potential dips below the baseline resting membrane potential, becoming more negative than $-70\,\text{mV}$ .
  - The membrane gradually returns to the baseline resting membrane potential ( $-70\,\text{mV}$ ) through passive leak currents and active transport.
Ion Transport Mechanisms:
- Ion Pumps:
  - Require energy in the form of ATP (active transport).
  - Function to move ions against their concentration gradients to restore and maintain chemical gradients.
- Ion Channels:
  - Require no metabolic energy (passive transport).
  - Allow ions to diffuse rapidly down existing electrochemical gradients upon opening.
Graded Potentials:
- Sub-threshold electrical changes whose amplitude varies with stimulus intensity.
- Excitatory Postsynaptic Potential (EPSP): A depolarizing graded potential that shifts the membrane closer to threshold.
- Inhibitory Postsynaptic Potential (IPSP): A hyperpolarizing graded potential that shifts the membrane further away from threshold.

Action potential voltage curve plotting membrane potential in millivolts against time across resting, depolarizing, repolarizing, and hyperpolarizing phases

Mechanisms of Action Potential Propagation

Local Current Generation:
- The localized entry of $\text{Na}^+$ ions into the axon creates a local electrical current inside the axoplasm.
- This positive internal charge spreads laterally along the interior surface of the membrane.
Successive Depolarization:
- As the local current spreads laterally, it depolarizes the adjacent areas of the inactive axonal membrane.
- When this adjacent membrane region is depolarized to the threshold value ( $-55\,\text{mV}$ ), voltage-gated $\text{Na}^+$ channels located in the new region of the membrane are triggered to open.
- The entry of $\text{Na}^+$ into this new region generates another local current, repeating the cycle in downstream segments.
Continuous Propagation Characteristics:
- Once initiated, the wave of depolarization moves along the entire length of the neuronal axonal membrane.
- The signal travels continuously at a rate of approximately $10\,\text{m/s}$ in unmyelinated fibers.
- The propagation operates by continuously "re-triggering" identical action potentials in consecutive adjacent patches of membrane.
- The impulse propagates along the axon until it reaches the synaptic end bulb (axon terminal).

Refractory Period and Directional Control

Role in Unidirectional Conduction:
- Action potentials travel strictly in one direction along the axon, proceeding from the axon hillock toward the axon terminal.
- The refractory period provides the fundamental mechanism that prevents backwards (retrograde) transmission.
- Because the upstream patch of membrane that just fired is temporarily in an absolute or relative refractory state (due to $\text{Na}^+$ channel inactivation and delayed $\text{K}^+$ channel closure), lateral current cannot re-excite it.
Functional Significance:
- Establishes Maximum Frequency: Sets an upper limit on the maximum rate (frequency) at which a neuron can generate action potentials.
- Governs Propagation Characteristics: Influences the spacing, timing, and refractory recovery between successive traveling impulses.
- Guarantees Forward Propagation: Enforces fidelity of signal transmission strictly from the trigger zone (axon hillock) to the axon terminal.

Factors Governing Conduction Velocity

Axon Diameter:
- Larger axon diameter results in faster propagation velocity ("larger = faster").
- Mechanism: As the axonal diameter increases, the cross-sectional area expands, which decreases the internal electrical resistance to current flow within the axoplasm.
Myelination:
- Specialized glial cells wrap around axonal segments to form a multilayered, lipid-rich insulating sheath.
- Central Nervous System (CNS): Myelin is produced by oligodendrocytes.
- Peripheral Nervous System (PNS): Myelin is produced by Schwann cells (noted as shwan cells).
- Functional Impact: Myelin insulation dramatically increases the velocity of action potential propagation along the axon.
Saltatory Conduction:
- The myelin sheath is discontinuous, interrupted at regular intervals by exposed nodal regions (nodes of Ranvier).
- Electrical charge flows rapidly through the insulated internodes by electrotonic conduction without ion leakage across the membrane.
- The action potential regenerates only at the unmyelinated nodes, appearing to "jump" from node to node.
Demyelination Pathology:
- In demyelinating conditions, the loss or absence of the protective myelin insulation permits current leakage across the membrane.
- Electrotonic conduction (noted as electronic conduction) degrades over distance and cannot maintain sufficient voltage to reach and depolarize the next downstream node to threshold.
- Consequence: The action potential fails to regenerate and conduction ceases ("action potential fails").

Synaptic Transmission and Signal Transduction

Definition:
- Synaptic transmission is the physiological process through which an electrical signal is transmitted from one excitable cell to another across a specialized junction (synapse).
Sequential Steps in Synaptic Transmission:
- Presynaptic Influx: The arrival of an action potential at the synaptic end bulb depolarizes the axon terminal membrane, prompting voltage-gated calcium channels to open and allowing $\text{Ca}^{2+}$ to enter.
- Vesicle Fusion and Exocytosis: Intracellular $\text{Ca}^{2+}$ triggers synaptic vesicles laden with neurotransmitters to fuse with the presynaptic membrane.
- Cleft Diffusion: Neurotransmitters are released into the synaptic cleft and diffuse across the extracellular space.
- Receptor Binding: Neurotransmitters bind to specific post-synaptic receptor proteins embedded in the membrane of the postsynaptic neuron.
Tri-Phasic Signal Transformation:
- Transmission proceeds through three distinct phases: $\text{Action Potential (Electrical)} \rightarrow \text{Neurotransmitters (Chemical)} \rightarrow \text{Receptors} \rightarrow \text{Graded Potential (Electrical)}$

Anatomical diagram of a synapse displaying pre-synaptic neuron terminal, calcium influx, neurotransmitter release across the cleft, and post-synaptic receptors

Postsynaptic Potentials and Summation Mechanics

Postsynaptic Electrical Events:
- Excitatory Postsynaptic Potential (EPSP):
  - Occurs when neurotransmitter binding triggers the opening of cation channels, allowing $\text{Na}^+$ to enter ( $\text{Na}^+\text{ enters}$ ).
  - Produces a localized depolarizing graded potential, shifting the postsynaptic membrane potential closer to threshold.
- Inhibitory Postsynaptic Potential (IPSP):
  - Occurs when neurotransmitter binding prompts potassium ions to leave ( $\text{K}^+\text{ leave}$ ) or chloride ions to enter ( $\text{Cl}^-\text{ enters}$ ).
  - Produces a localized hyperpolarizing graded potential, shifting the postsynaptic membrane potential further below resting potential and away from threshold.
Integration at the Trigger Zone:
- Individual postsynaptic potentials are graded and dissipate over distance.
- To initiate an all-or-none action potential, graded potentials must summate at the axon hillock, which serves as the neuronal trigger zone.
Spatial Summation:
- Occurs when input signals originating simultaneously from multiple distinct presynaptic neurons add up at the trigger zone (axon hillock).
- Multiple concurrent EPSPs combine algebraically to drive the membrane potential to threshold.
Temporal Summation:
- Occurs when an increased frequency of successive action potentials arrives from a single presynaptic neuron.
- The postsynaptic potentials occur in rapid succession before previous ones decay, adding up over time at the trigger zone to reach threshold.

Postsynaptic Receptor Classifications

Ionotropic Receptors:
- Structure: The receptor macromolecule is itself an ion channel (ligand-gated / channel-linked).
- Functional Kinetics: Exhibit very fast onset and rapid channel gating upon ligand binding.
- Directly regulate ion flux across the postsynaptic membrane to produce immediate postsynaptic potentials.
Metabotropic Receptors:
- Structure: The receptor is physically separate from ion channels and functions as a G-protein coupled receptor (GPCR).
- Functional Kinetics: Mediate slower-onset, longer-lasting cellular effects.
- Operate via secondary messenger cascades and intracellular signaling mechanisms.
- Directly modulate and alter cellular metabolism within the downstream cell (noted in transcript OCR as "clown stream cell").