6.2 Action Potential Propagation and Synaptic Transmission

6.2 Action Potential Kinetics and Synaptic Transmission Dynamics

Ionic Basis of the Action Potential Waveform

An action potential is a rapid, transient, all-or-none electrical reversal of membrane potential across excitable membranes (neurons and muscle cells). The waveform is produced by sequential opening and closing of voltage-gated ion channels.

• Resting State (-70 mV): Membrane potential maintained primarily by background $K^+$ leak channels and the $Na^+/K^+$ ATPase. Voltage-gated $Na^+$ channels ($Na_v$) have their activation gates ($m$-gates) closed and inactivation gates ($h$-gates) open. Voltage-gated $K^+$ channels ($K_v$) have their activation gates ($n$-gates) closed.
• Depolarization Threshold (-55 mV): Local graded depolarizing stimuli (e.g., EPSPs) bring $V_m$ to the critical firing threshold (-55 mV). This threshold voltage triggers rapid opening of $Na_v$ activation ($m$) gates.
• Rapid Depolarization Phase: $Na^+$ influx surges down its steep electrochemical gradient ($E_{Na} \approx +65\text{ mV}$). This induces a regenerative positive feedback cycle (Hodgkin cycle): $Na^+$ influx causes further depolarization, which opens adjacent $Na_v$ channels. Membrane potential shoots rapidly upward toward $+30\text{ mV}$.
• Peak and Overshoot (+30 mV): Two critical channel gating events occur simultaneously at peak potential:
  1. Time-dependent closure of $Na_v$ inactivation ($h$) gates, halting further $Na^+$ influx.
  2. Delayed opening of voltage-gated $K^+$ channel activation ($n$) gates (delayed rectifier $K_v$ channels).
• Repolarization Phase: $Na^+$ conductance drops to zero while $K^+$ efflux surges down its electrochemical gradient ($E_K \approx -90\text{ mV}$), rapidly driving $V_m$ back toward negative values.
• After-Hyperpolarization (Undershoot Phase): $K_v$ channels close slowly. The sustained high $K^+$ conductance causes $V_m$ to transiently hyperpolarize beyond resting potential, approaching $E_{K^+}$ (around $-85\text{ to } -90\text{ mV}$). As $K_v$ channels complete closure, background leak channels restore $V_m$ to the resting level of $-70\text{ mV}$.

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Refractory Periods: Absolute vs. Relative

Refractory periods restrict action potential frequency and enforce unidirectional propagation along axonal membranes.

Absolute Refractory Period (ARP)

• Timeframe: Spans from threshold onset through the majority of repolarization.
• Molecular Mechanism: Voltage-gated $Na^+$ channels are either already open or closed in an inactivated state ($h$-gate closed). A channel with a closed $h$-gate cannot be opened by any stimulus, regardless of intensity.
• Physiological Significance: Ensures an action potential cannot re-excite recently depolarized membrane, forcing propagation forward (unidirectional) away from the soma toward the axon terminal. Sets the theoretical upper limit on neuronal firing frequency ($\sim 1000\text{ Hz}$).

Relative Refractory Period (RRP)

• Timeframe: Follows the ARP, spanning late repolarization through the after-hyperpolarization phase.
• Molecular Mechanism: A portion of $Na_v$ channels have reset (activation gate closed, inactivation gate reopened), but $K_v$ channels remain open, producing elevated $K^+$ conductance and membrane hyperpolarization.
• Requirement: A suprathreshold (larger than normal) depolarizing stimulus is required to recruit sufficient reset $Na_v$ channels and overcome outward $K^+$ efflux to reach firing threshold.

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Biomechanics of Axonal Conduction Velocity

Conduction velocity ($v$) determines the transmission speed of signals along an axon and depends directly on core physical cable properties:

• Axon Diameter: Increasing axon diameter increases cross-sectional area, which dramatically reduces internal axial resistance ($R_i$). Lower $R_i$ allows depolarizing local current to flow faster and farther down the axon interior. In unmyelinated axons, conduction velocity scales with the square root of diameter ($v \propto \sqrt{\text{diameter}}$).
• Myelination: Formed by Schwann cells in the Peripheral Nervous System (PNS) and Oligodendrocytes in the Central Nervous System (CNS).
  • Myelin sheaths wrap tightly around axolemma, acting as electrical insulators that dramatically increase membrane resistance ($R_m$, reducing current leakage) and decrease membrane capacitance ($C_m$, reducing charge stored across lipid bilayer).
• Nodes of Ranvier and Saltatory Conduction:
  • Nodes of Ranvier are unmyelinated gaps ($1-2\text{ }\mu\text{m}$) situated between myelinated internodes, densely packed with voltage-gated $Na^+$ channels ($Na_v 1.6$).
  • Action potentials jump from node to node (saltatory conduction), bypassing insulated internodes.
  • Benefits: Increases conduction velocity up to $120\text{ m/s}$ (in large A-$\alpha$ sensory/motor nerve fibers) while conserving ATP, as $Na^+/K^+$ ATPase activity is confined primarily to nodal regions rather than the entire axolemma.

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Presynaptic Vesicular Exocytosis and Neurotoxins

Chemical synaptic transmission converts an electrical presynaptic action potential into a chemical signal across the synaptic cleft:

1. Presynaptic Depolarization: An action potential invading the presynaptic axon terminal depolarizes the terminal membrane.
2. $Ca^{2+}$ Influx: Depolarization opens voltage-gated $Ca^{2+}$ channels (N-type and P/Q-type). $Ca^{2+}$ surges down its steep $10,000$-fold electrochemical gradient into presynaptic active zones.
3. Calcium Sensor Activation: Incoming $Ca^{2+}$ binds synaptotagmin, a specialized vesicular transmembrane calcium-sensing protein.
4. SNARE Complex Assembly and Fusion: $Ca^{2+}$-activated synaptotagmin triggers conformational zippering of the SNARE complex:
   • v-SNARE: Synaptobrevin (VAMP) located on the synaptic vesicle membrane.
   • t-SNAREs: Syntaxin-1 and SNAP-25 located on the presynaptic plasma membrane.
   • The SNARE complex pulls the vesicle into intimate contact with the plasma membrane, opening a fusion pore to release neurotransmitters into the $20-40\text{ nm}$ synaptic cleft via exocytosis.

Clinical Neurotoxin Targets

• Botulinum Toxin (Clostridium botulinum): Endopeptidase light chain cleaves SNAP-25 or synaptobrevin at cholinergic neuromuscular junctions, blocking acetylcholine release $\rightarrow$ flaccid paralysis.
• Tetanus Toxin (Clostridium tetani): Taken up at motor endplates, undergoes retrograde axonal transport to spinal inhibitory interneurons (Renshaw cells), where it cleaves synaptobrevin, blocking release of GABA and glycine $\rightarrow$ disinhibition of motor neurons $\rightarrow$ spastic paralysis (lockjaw, risus sardonicus).

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Postsynaptic Receptors and Neurotransmitter Dynamics

Postsynaptic responses are governed by two distinct receptor classes:

• Ionotropic Receptors (Ligand-Gated Ion Channels): Direct, rapid transmission (millisecond kinetics).
  • Excitatory Postsynaptic Potentials (EPSPs): Cation-permeable channels ($Na^+, Ca^{2+}$ influx) depolarize the postsynaptic membrane (e.g., Nicotinic Acetylcholine Receptors [nAChR], AMPA and NMDA Glutamate Receptors).
  • Inhibitory Postsynaptic Potentials (IPSPs): Anion-permeable channels ($Cl^-$ influx) hyperpolarize the postsynaptic membrane (e.g., $GABA_A$ Receptors, Glycine Receptors).
• Metabotropic Receptors (G-Protein Coupled Receptors - GPCRs): Indirect, modulatory transmission (seconds to minutes) operating via second messenger cascades ($cAMP, IP_3/DAG$). Examples include Muscarinic Acetylcholine Receptors ($M_1-M_5$), Adrenergic Receptors ($\alpha_1, \alpha_2, \beta_1, \beta_2$), Metabotropic Glutamate (mGluR), and $GABA_B$ Receptors ($G_i$-coupled, opens $K^+$ channels).

Major Neurotransmitter Systems and Termination Pathways

• Acetylcholine (ACh): Primary neurotransmitter at NMJ, parasympathetic postganglionic, and sympathetic preganglionic neurons. Synthesized by Choline Acetyltransferase (ChAT). Cleared rapidly in synaptic cleft by Acetylcholinesterase (AChE) into choline and acetate.
• Glutamate: Principal excitatory neurotransmitter in the CNS. Cleared from the synaptic cleft by Excitatory Amino Acid Transporters (EAAT) into surrounding astrocytes, converted to glutamine by glutamine synthetase, and recycled back to neurons.
• GABA ($\gamma$-aminobutyric acid) and Glycine: Principal inhibitory neurotransmitters in brain (GABA) and spinal cord (Glycine). GABA is synthesized from glutamate by Glutamate Decarboxylase (GAD) (requiring Pyridoxal phosphate / Vitamin $B_6$ cofactor). Cleared by GAT transporters and degraded by GABA transaminase.
• Monoamines (Dopamine, Norepinephrine, Serotonin): Catecholamines (dopamine, norepinephrine, epinephrine derived from tyrosine) and serotonin (5-HT derived from tryptophan) are cleared primarily via presynaptic reuptake transporters (DAT, NET, SERT) and degraded intracellularly by Monoamine Oxidase (MAO) and Catechol-O-methyltransferase (COMT).