Action Potentials and Neuronal Communication

Neuronal Anatomy and Synaptic Organization

• Axon Initial Segment

  • The axon initial segment is the specific region of the cell where an action potential is first generated.

  • It is a non-condensed, non-ensemble region located at the start of the axon.

• Axon Collaterals, Convergence, and Divergence

  • Convergence: Dendrites provide convergence by receiving signals from multiple source neurons that all send their inputs onto a single target neuron.

  • Divergence: Axon collaterals provide divergence. An axon collateral can form several secondary branches, allowing a single neuron to innervate multiple downstream target neurons.

• Synaptic Structures and Terminology

  • Synapse: The structural terminal at the end of a neuronal process that releases neurotransmitters onto the surface of a target cell.

  • Synaptic Cleft: The tiny fluid-filled space between the presynaptic terminal and the postsynaptic cell, measuring approximately $20\,\text{nm}$ to $30\,\text{nm}$ across.

  • Presynaptic vs. Postsynaptic Relays: Terminology depends on the relative direction of signal transmission:

    • If a yellow neuron signals to a green neuron, the yellow neuron is presynaptic to the green neuron, and the green neuron is postsynaptic to the yellow neuron.

    • If that same green neuron then signals to a purple neuron, the green neuron acts as the presynaptic neuron for the purple neuron, while the purple neuron is postsynaptic to the green neuron.

• Glial Cells and Myelination

  • Schwann Cells: Located in the Peripheral Nervous System (PNS). Individual Schwann cells wrap around axons multiple times to provide electrical insulation necessary for high-speed action potential propagation.

  • Oligodendrocytes: Located in the Central Nervous System (CNS). Small cells that perform essentially the same insulating and wrapping functions as Schwann cells to facilitate action potential propagation.

Biophysics of Membrane Potentials and Voltage-Gated Channels

• Action Potential Waveform Overview

  • Resting Membrane Potential: Typically established at $-70\,\text{mV}$.

  • Time Course: The entire action potential dynamic occurs rapidly, lasting between $1\,\text{ms}$ and $2\,\text{ms}$.

  • Depolarization Phase: The rapid upward deflection of the membrane potential from negative values toward positive values.

  • Repolarization Phase: The rapid downward deflection of the membrane potential back toward negative resting levels.

  • After-Hyperpolarization: A transient phase during which the membrane potential falls below the normal resting level (more negative than $-70\,\text{mV}$) for a couple of milliseconds before returning to baseline.

• Passive vs. Active Membrane Responses (Ohm's Law)

  • Experimental Stimulation: Applied using square-wave electrical currents injected directly into the cell via a microelectrode.

  • Hyperpolarization: Injection of negative current produces a passive hyperpolarizing response.

  • Sub-threshold Depolarization: Injection of positive current produces a passive depolarizing response. As the intensity of the injected positive current increases, the amplitude of the resulting passive depolarization increases proportionally.

  • Ohm's Law: Sub-threshold passive electrical behavior and voltage changes across the cell membrane conform to standard physical electrical principles described by Ohm's Law ($V = I \times R$).

• Threshold Potential

  • When the membrane potential is artificially or naturally depolarized to values more positive than the threshold level of $-55\,\text{mV}$ to $-50\,\text{mV}$, passive responses transition into an active, self-regenerating action potential.

Molecular Mechanisms of Sodium and Potassium Gated Channels

• Voltage-Gated Sodium Channels ($\text{Na}^+$ Channels)

  • Activation Threshold: These channels contain a voltage sensor sensitive to depolarization. When the membrane potential reaches approximately $-50\,\text{mV}$ to $-55\,\text{mV}$, the activation gates open.

  • Driving Force: Opening allows sodium ions ($\text{Na}^+$) to enter the cell down their electrochemical gradient. The theoretical equilibrium potential for sodium ($E_{\text{Na}}$) is $+59\,\text{mV}$.

  • Positive Feedback Mechanism (Hodgkin Cycle):

    1. Initial depolarization reaches the threshold of $-55\,\text{mV}$.

    2. Voltage-gated $\text{Na}^+$ channels open, increasing $\text{Na}^+$ conductance.

    3. Influx of positively charged $\text{Na}^+$ ions produces further membrane depolarization.

    4. This additional depolarization recruits and opens adjacent voltage-gated $\text{Na}^+$ channels.

    5. This self-reinforcing, exponential cycle continues driving the membrane potential upward.

  • Inactivation Gate: At approximately $+30\,\text{mV}$, a time-dependent inactivation gate closes the channel lumen.

    • Even though the activation gate remains open, the channel enters an inactive, non-conducting state.

    • This rapid inactivation halts $\text{Na}^+$ influx, preventing the membrane potential from ever fully reaching the $\text{Na}^+$ equilibrium potential of $+59\,\text{mV}$.

• Voltage-Gated Potassium Channels ($\text{K}^+$ Channels)

  • Delayed Rectifier Kinetics: Voltage-gated $\text{K}^+$ channels are also triggered by depolarization around $-55\,\text{mV}$, but they exhibit delayed opening kinetics (opening approximately $0.5\,\text{ms}$ to $1.0\,\text{ms}$ after $\text{Na}^+$ channels open).

  • Driving Force: The equilibrium potential for potassium ($E_{\text{K}}$) is $-89\,\text{mV}$. While the driving force is moderate at $-70\,\text{mV}$ (a $19\,\text{mV}$ difference), at $+30\,\text{mV}$ the driving force is extremely high (a $119\,\text{mV}$ difference), driving rapid $\text{K}^+$ efflux.

  • Repolarization Dynamic: Delayed $\text{K}^+$ channels open fully right around the time $\text{Na}^+$ channel inactivation gates close ($+30\,\text{mV}$). Efflux of positive $\text{K}^+$ ions drives the membrane potential rapidly back toward negative values.

  • Channel Resetting and Hyperpolarization:

    • As repolarization drops the membrane potential back below the $-55\,\text{mV}$ threshold, $\text{Na}^+$ channel inactivation gates reopen while their activation gates close, returning $\text{Na}^+$ channels to a resting closed state capable of re-activation.

    • Because voltage-gated $\text{K}^+$ channels close slowly and do not shut instantaneously when threshold is crossed, excess efflux of $\text{K}^+$ ions causes after-hyperpolarization (falling below $-70\,\text{mV}$).

    • As $\text{K}^+$ channels finish closing, $\text{K}^+$ conductance returns to baseline, restoring the resting membrane potential to $-70\,\text{mV}$.

• Probabilistic Properties and Kinetics

  • Ion channel opening is a probabilistic event; individual channels do not open simultaneously.

  • Opening and closing kinetics follow exponential curves, which appears visually as a gradual slope rather than an instantaneous vertical step on voltage and conductance graphs.

• Pharmacology and Cell-Type Variations

  • Tetrodotoxin (TTX): A potent neurotoxin obtained from pufferfish (commonly used in Japan to prepare sushi, requiring specially trained cooks). TTX selectively blocks voltage-gated $\text{Na}^+$ channels, completely preventing action potential generation.

  • Action Potential Diversity Across Tissues:

    • Action potential duration and shape vary between tissue types due to differential expression profiles of ion channel subtypes.

    • Neurons vs. Skeletal Muscle: Exhibit subtle differences in waveform duration and channel density.

    • Cardiac Muscle Cells: Display a prolonged action potential profile due to significant contributions from voltage-gated calcium ($\text{Ca}^{2+}$) channels in addition to $\text{Na}^+$ and $\text{K}^+$ channels.

Refractory Periods and Action Potential Propagation

• Refractory Periods

  • Total Amplitude: The overall amplitude of a standard neuronal action potential is approximately $100\,\text{mV}$ (spanning from $-70\,\text{mV}$ to $+30\,\text{mV}$).

  • Absolute Refractory Period:

    • Duration: Approximately $1\,\text{ms}$.

    • Mechanism: Begins at $+30\,\text{mV}$ when $\text{Na}^+$ channel inactivation gates close.

    • Functional Effect: It is physically impossible to elicit a second action potential during this window, regardless of how intense a second stimulus is applied, because $\text{Na}^+$ channels are completely inactive.

  • Relative Refractory Period:

    • Duration: Spans from approximately $10\,\text{ms}$ to $20\,\text{ms}$ in neuronal and muscle tissue following the absolute refractory period.

    • Mechanism: $\text{Na}^+$ channels have transitioned back to their closed-activatable state, but voltage-gated $\text{K}^+$ channels remain open (causing outward positive current) and the membrane may be hyperpolarized.

    • Functional Effect: A second action potential can be generated, but it requires a significantly higher stimulus intensity to overcome the opposing outward $\text{K}^+$ current and hyperpolarized state.

    • Frequency Control: The total duration of the absolute and relative refractory periods sets an upper limit on the maximum firing frequency of action potentials (e.g., limiting theoretical maximal frequency to around $1000\,\text{Hz}$ depending on absolute recovery time).

• Propagation Dynamics Along Axons

  • Local Current Flow: Generation of an action potential in one region produces localized passive current flow that spreads to adjacent inactive membrane segments, depolarizing them to threshold.

  • Three-Segment Axonal Model:

    • Time Period 1: Segment 1 reaches action potential peak ($+30\,\text{mV}$). Passive local current spreads to Segment 2, bringing it to initial threshold ($-55\,\text{mV}$). Segment 3 remains unaffected.

    • Time Period 2: Segment 1 enters repolarization. Segment 2 reaches action potential peak ($+30\,\text{mV}$). Passive local current spreads from Segment 2 to Segment 3, initiating threshold depolarization in Segment 3.

    • Time Period 3: Segment 1 is fully repolarized and restored. Segment 2 undergoes repolarization. Segment 3 reaches its action potential peak.

  • Unidirectional Propagation:

    • In neurons, action potentials originate at the axon hillock/initial segment and travel strictly unidirectionally down the axon toward the terminals.

    • Unidirectional travel is enforced by the refractory period: backward propagation (back-propagation) is prevented because upstream membrane segments that just fired are in an absolute refractory state.

    • Comparison with Muscle Cells: In muscle cells, synapses are situated centrally; action potentials originate in the middle of the cell and propagate bidirectionally toward both ends to trigger muscular contraction.

Student Dialogue, Class Announcements, and Group Photo Logistics

• Quiz and Academic Discussions

  • Students discussed quiz questions numbered $137$ to $40$ popping up on sidebar notifications during class.

  • Mention of standard procedures requiring students to hand in or hold onto their phones during exam periods.

• Group Photo Logistics and Location Changes

  • Due to high temperatures outside and space constraints, class photo logistics were coordinated to move to the Allied Health building next door.

  • Instructions given over the microphone directing all Allied Health and Pharmacy students to relocate to the Allied Health building stairs for the photo.

  • Arrangement guidelines: Taller individuals requested to position themselves toward the back or front step group to ensure proper elevation and visibility.

  • Building address noted as $111$ during discussions about location choices.

• Personal Travel and Class Comments

  • Student expression of extreme hunger leading to skipping a group study session.

  • Personal anecdote regarding travel: Driving to Tulsa described as a "nasty drive" that is strongly disliked compared to weekend trips home.

  • Photo submission process: Group photos collected annually via email to calculate class percentile participation records.