Lecture 6 Physiology Module 3

Administrative Announcements

• Exam 2 Evaluation: Exam 2 grades have been officially posted, accompanied by an eClass announcement.
• Exam Review Session: An exam review session is scheduled for Friday afternoon; students requiring review should consult eClass for specific timing and scheduling details.
• Semester Progression: Exactly four to five content lectures remain prior to the administration of Exam 3.

Principles of Action Potential Propagation: Contiguous vs. Saltatory Conduction

• Contiguous Conduction in Unmyelinated Axons:

  • Occurs exclusively in unmyelinated neurons.
  • Requires continuous, de novo regeneration of the action potential across every consecutive, adjacent patch of the axonal plasma membrane.
  • Current flows from the active depolarized site to immediately adjacent inactive sites down the length of the axon, originating at the axon hillock and terminating at the output zone.

• Myelination Architecture and Glial Cell Subtypes:

  • Myelin Sheath: A thick, concentric, multi-layered fatty wrapping encasing the neuronal axon that provides electrical insulation from the surrounding extracellular fluid ($\text{ECF}$). Constitutes the white matter within the central nervous system ($\text{CNS}$).
  • Peripheral Nervous System ($\text{PNS}$): Myelination is performed by Schwann cells. Each individual wrapping along an axon corresponds to a single Schwann cell possessing its own nucleus and cellular machinery.
  • Central Nervous System ($\text{CNS}$): Myelination is executed by oligodendrocytes. These are larger, more complex glial cells capable of extending multiple cytoplasmic processes to wrap and myelinate segments of several distinct neuronal axons simultaneously.

• Nodes of Ranvier:

  • Specialized, uninsulated gaps situated at regular intervals between adjacent segments of myelin.
  • Spatial Dimensions:
  • Myelinated internodal segments span approximately $1\,\text{mm}$ in length.
  • Each Node of Ranvier forms an exposed gap of approximately $2\,\mu\text{m}$ ($2\,\text{microns}$).
  • Ion Channel Localization: Voltage-gated $Na^+$ channels are heavily concentrated at the Nodes of Ranvier. Voltage-gated channels are functionally absent beneath the insulated internodal myelin sheath because the physical barrier isolates the axolemma from the $\text{ECF}$, preventing trans-membrane ion flux.

• Mechanism of Saltatory Conduction:

  • Occurs in myelinated neurons, where the electrical impulse actively "jumps" from one Node of Ranvier to the subsequent node.
  • When an explosive depolarization phase occurs at an active node, influx of $Na^+$ creates a local accumulation of positive charge within the intracellular fluid ($\text{ICF}$).
  • The high electrical insulation of the internodal myelin prevents ionic leakage of $Na^+$ out across the axolemma.
  • This structural insulation preserves the electrical current, enabling positive charge to travel rapidly and electrotonically down the interior of the axon across the $1\,\text{mm}$ internode with sufficient magnitude to depolarize the membrane of the adjacent Node of Ranvier to threshold potential.
  • Upon reaching threshold, the subsequent node undergoes explosive depolarization via its own dense cluster of voltage-gated $Na^+$ channels, regenerating the full action potential.

Determinants of Neuronal Conduction Velocity

• Conduction Velocity Overview: Conduction velocity measures the speed at which an initiated action potential propagates along an axon from the axon hillock to the terminal output zone.

• Primary Determinants of Conduction Velocity:

  • 1. Myelination Status:
  • Saltatory conduction in myelinated axons increases conduction velocity by up to $50$ times ($50\times$) compared to contiguous conduction in unmyelinated fibers.
  • Bypassing continuous membrane regeneration substantially shortens the transit time of the electrical signal.
  • 2. Axonal Diameter:
  • Governed by internal electrical resistance to ion movement.
  • Large-diameter fibers present a significantly lower internal resistance ($R$) to electrical current flow than small-diameter fibers, providing greater cross-sectional area and space for ions to travel axially.
  • Larger axonal diameter directly correlates with elevated conduction velocity.

• Physiological Comparisons of Conduction Velocity:

  • Unmyelinated Human Visceral Fibers: Fibers innervating the digestive tract exhibit small diameters and lack myelination, yielding conduction velocities of less than $1\,\text{m/s}$. Digestive motility does not require instantaneous temporal responses.
  • Unmyelinated Giant Squid Axon: Possesses an extraordinarily large axonal diameter (sufficiently wide for early electrophysiologists to insert intracellular electrodes), enabling conduction velocities of $25\,\text{m/s}$ despite completely lacking myelin.
  • Myelinated Human Somatic Motor Neurons: Every alpha motor neuron innervating skeletal muscle is heavily myelinated and possesses a large diameter. The combination of saltatory conduction and low internal resistance produces conduction speeds that vastly exceed the $25\,\text{m/s}$ velocity of the giant squid, ensuring rapid motor reflexes in response to environmental stimuli.

• Clinical Pathophysiology: Multiple Sclerosis ($\text{MS}$):

  • An autoimmune neurodegenerative disorder characterized by progressive immune-mediated destruction and loss of the myelin sheath within the central nervous system.
  • Consequences of Demyelination:
  • Uncovering previously insulated axonal segments exposes bare axolemma to the $\text{ECF}$.
  • Because the internodal axolemma lacks an adequate density of voltage-gated $Na^+$ channels, the entering intracellular $Na^+$ rapidly leaks across the bare membrane.
  • The electrical impulse loses its driving potential, dramatically slowing conduction velocity.
  • In advanced stages, demyelination induces complete conduction block, where the depolarizing current dissipates entirely before reaching the next node, preventing downstream action potential regeneration and causing severe motor and sensory impairments.

Structural and Functional Organization of the Synapse

• Definition of a Synapse: The specialized anatomical junction mediating functional communication between the output zone of one neuron and the input zone of a target neuron.

• Structural Anatomy of the Chemical Synapse:

  • Presynaptic Neuron: The upstream neuron delivering the signal via its axon terminal (also designated as the synaptic knob or terminal footing).
  • Postsynaptic Neuron: The downstream target neuron receiving the signal at its input zone, which comprises the dendrites and the cell body (soma).
  • Subsynaptic Membrane: The specialized domain of the postsynaptic plasma membrane directly confronting the presynaptic terminal, rich in chemically gated ion channel receptors.
  • Synaptic Cleft: An extracellular physical barrier separating the presynaptic membrane and postsynaptic subsynaptic membrane.
  • Possesses an ultra-narrow gap measured on the scale of nanometers ($\text{nm}$).
  • Because there is no cytoplasmic or physical continuity between the two cellular membranes, an electrical action potential cannot propagate directly across the cleft.

• Synaptic Integration and Convergence:

  • A single postsynaptic neuron possesses expansive dendritic arbors and soma surfaces designed to maximize receptive surface area.
  • A single postsynaptic neuron can receive inputs from up to $100{,}000$ individual synaptic terminals.

• Directional Relativity in Neuronal Circuits:

  • Synaptic nomenclature is strictly relative to the specific junction under examination.
  • In a multisynaptic chain, an intermediate neuron acts as the postsynaptic target for preceding upstream neurons and simultaneously functions as the presynaptic transmission source for subsequent downstream neurons.

• Classification of Synapses:

  • Electrical Synapses: Joined by gap junctions providing direct electrical continuity; characteristic of cardiac muscle and specific smooth muscle tissues.
  • Chemical Synapses: Predominant synaptic modality in the nervous system, utilizing chemical messengers (neurotransmitters) to bridge the physical gap of the synaptic cleft.

• Fundamental Purpose of the Action Potential:

  • The sole functional outcome of action potential propagation along the axon is to trigger the controlled exocytosis of neurotransmitters from the synaptic vesicles housed within the axon terminal.

Molecular Mechanisms of Neurotransmitter Release and Chemical Synaptic Transmission

• Conversion of Neuronal Signaling Modalities:

  • Chemical synaptic transmission executes a precise triphasic conversion of signaling:
  • $1.$ Electrical Signal (action potential traveling down presynaptic axon).
  • $2.$ Chemical Signal (neurotransmitter exocytosis and diffusion across synaptic cleft).
  • $3.$ Electrical Signal (graded potential generation within postsynaptic subsynaptic membrane).

• Step-by-Step Mechanism of Neurotransmitter Release:

  • Step 1: Arrival of the Depolarizing Wave: The action potential propagates into the presynaptic terminal footing (synaptic knob), causing membrane depolarization via voltage-gated $Na^+$ influx.
  • Step 2: Voltage-Gated Calcium Influx: The localized depolarization triggers the conformational opening of voltage-gated $Ca^{2+}$ channels localized along the presynaptic active zone membrane. Given the steep chemical concentration gradient (significantly higher $Ca^{2+}$ concentration in the $\text{ECF}$ relative to the $\text{ICF}$), $Ca^{2+}$ rushes into the synaptic knob.
  • Step 3: Synaptic Vesicle Priming and SNARE Proteins: Membrane-delimited synaptic vesicles packed with neurotransmitters are sequestered at the presynaptic terminal, maintained in a loosely docked state adjacent to the plasma membrane by a complex of membrane-bound proteins known as SNARE proteins.
  • Step 4: Calcium Sensing via Synaptotagmin:
  • Synaptotagmin serves as the dedicated intracellular $Ca^{2+}$ sensor located on the vesicle membrane.
  • Intracellular $Ca^{2+}$ ions bind directly to specific coordination binding sites on synaptotagmin.
  • Step 5: Tight SNARE Wrapping and Membrane Fusion:
  • Calcium binding induces an immediate conformational change in synaptotagmin.
  • Synaptotagmin forces the loosely associated SNARE proteins to wrap and coil around one another with high affinity and tension.
  • This tight wrapping draws the lipid bilayer of the synaptic vesicle into direct, physical apposition with the presynaptic plasma membrane, overcoming the electrostatic repulsion of their polar headgroups.
  • Step 6: Exocytosis: The vesicle membrane fuses into the presynaptic cell membrane, opening a pore that expels the neurotransmitter contents directly into the synaptic cleft via exocytosis.

• Postsynaptic Activation and Graded Potential Generation:

  • Following exocytosis, neurotransmitter molecules passively diffuse across the nanometer-scale synaptic cleft toward the subsynaptic membrane.
  • Neurotransmitters reversibly bind to specific receptor binding sites on chemically gated ion channels (ligand-gated channels).
  • Receptor engagement triggers channel gating from a closed to an open conformation.
  • If the channel is a chemically gated $Na^+$ channel, $Na^+$ enters the postsynaptic cell down its electrochemical gradient, causing a local depolarizing graded potential.
  • Graded potentials spread electrotonically along the dendritic and somatic plasma membrane toward the axon hillock.
  • If the graded potential delivers sufficient depolarizing current to reach threshold potential at the axon hillock, an action potential is triggered in the postsynaptic neuron.

Questions & Discussion

• Query on Sodium Leakage and Signal Strength:

  • Question: In an unmyelinated neuron, does sodium leak out and diminish potential strength, whereas in a myelinated neuron, insulation prevents sodium loss so signal strength is preserved between nodes?
  • Response: Yes. In an unmyelinated neuron, current leaks continuously across the uninsulated membrane, requiring localized channel opening at each patch to avoid signal decay. In a myelinated neuron, the myelin acts as a physical insulator preventing charge dissipation into the $\text{ECF}$. This allows the inward $Na^+$ current entering at one node to travel internally across the $1\,\text{mm}$ internodal distance without losing the threshold-level amplitude required to activate the subsequent node. Without myelin, sodium leakage would prevent downstream regeneration.

• Query on Threshold and Single Action Potential Sufficiency:

  • Question: Is the neurotransmitter released by the arrival of a single presynaptic action potential sufficient to generate an action potential in the postsynaptic neuron?
  • Response: No. Graded potentials vary continuously in magnitude and duration relative to the volume of neurotransmitter released. A single presynaptic action potential releases a finite quantum of neurotransmitter that produces a localized graded potential insufficient to reach threshold alone. Generating a postsynaptic action potential requires the integration and summation of numerous inputs across time or across multiple synapses, which is why individual neurons possess dendritic surfaces capable of accommodating up to $100{,}000$ simultaneous synaptic connections.

• Query on the Direct Role of Calcium in Fusion:

  • Question: Does calcium itself physically fuse with the membrane, or does it serve as an activating trigger?
  • Response: Calcium does not fuse with the membrane; it acts strictly as an intracellular chemical trigger. Calcium binds directly to high-affinity binding sites on the sensor protein synaptotagmin. This binding event initiates a conformational change that causes the loosely bound SNARE proteins to coil tightly together, mechanically pulling the synaptic vesicle into direct contact with the presynaptic plasma membrane to induce lipid bilayer fusion and exocytosis.