Lecture 6 - Neuro 3; AP, Refractory period, Myelin, Synapses, Ca2+

How many refractory periods in an action potential?

• 2

  • Absolute and relative

Absolute refractory period

• Time during which another AP can’t be triggered

  • No matter the stimulus strength

  • Occurs form the onset of AP (start of depolaritzation) until end of Na+ inactivation (end of repolarization)

• Why it happens (key mechanism)

  • Voltage-gated Na⁺ channels are INACTIVATED

  • The inactivation gate physically blocks the channel

  • Channel cannot reopen until the membrane repolarizes

Relative refractory period

• Time during which a stronger stimulus is necessary to trigger an AP

  • More depolarizing current is required to reach threshold

  • Due to hyperpolarization

    • If we were to get a stimulus of the same size that triggers a normal action potential → no AP fired, because, we are starting more negative than usual, and therefore need a more positive signal

  • Two things are happening:

    1. Some Na⁺ channels are still inactivated

    • Fewer available Na⁺ channels

    • Harder to reach threshold

    2. K⁺ channels are still open

    • High K⁺ permeability

    • Vm is hyperpolarized (more negative than RMP)

    → Threshold is effectively farther away

Action potential depolarization spread

• AP spread from the Axon hillock to the Axon terminal

• Signals spread through myelin sheaths, fire an AP at each Node of Ranvier, where Voltage-gated channels are concentrated at

  • All AP have same shape because there are the same Voltage gated Na+ and K+ down the axon, which determine its shape

• AP spreads DOWN in ONE DIRECTION

  • Absolute refractory period prevents the AP from going backwards, since Na+ channels behind the AP are inactivated and can’t reopen immediately

Na+ Channels flow

• When Na+ ions flow in, positive current flows passively in both directions

  • Passive current spread in both directions

    • Depolarizes the Na+ voltage channels forward and backwards, but Na+ channels backwards can’t open since they’ve been inactivated

AP potentials stereotypes durations and amplitude - Stimulus strength?

• AP all look the same

  • Same height

• Stimulus strength is indicated by AP frequency

  • Stronger stimulus = more frequent AP

  • Weaker stimulus = less frequent AP

Subthreshold stimulus gives…

• 0 AP

Brief threshold stimulus gives…

• 1 AP

Sustained stimulus gives…

• Multiple AP

Suprathreshold stimulus

• A stimulus strong enough to depolarize the membrane past threshold, even during the relative refractory period

• During sustained input → higher firing frequency

No hyperpolarization between spikes?

• Stimulus’s current overpowers the hyperpolarization and keep the AP at depolarization

  • Spiking immediately after Absolute, enough stimulus to overcome Relative

Myelinated Axons

• Myelin sheath insulates regions of the axon

  • Prevents ions from leaving the cytoplasm

  • Restricts action potential to Nodes of Ranvier

    • Current passively flows through myelinated areas

• Myelination increases length constant

• Motor neurons tend to have long myelinated axons

• Long, want fast signals

Myelination effect on Length constant

• Myelination changes resistance of the membrane, increasing the length constant

  • Allows signal to travel distance without decaying

• 𝜆 = length constance

• rm = membrane resistance

• ri = intracellular resistance

  • More myelinated and bigger axon diameter = faster

Saltatory conduction

• Signal travels faster through internodes than at Nodes of Ranvier

• Each AP takes same amount of time

  • Heavily myelinated: 15-150 m/s

  • Lightly myelinated: 3-15 m/s

  • Unmyelinated: 1 m/s

    • Triggers AP in directly adjacent region

    • Will have more Voltage-gated ion channels in total

• Can’t just myelinate the whole axon, since need AP to “re-up” current at each point

Passive current / Electrotonic spread vs AP

• Passive current decreases with distance

  • Signal strength decreases over distance from site of stimulation

• AP maintains amplitude

  • AP require more time to occur but maintain amplitude

Increase diameter of axon

• Larger-diameter axons increase AP conduction speed

  • Changes intracellular resistance

• Increase length constant - allows current to spread farther and decay more slowly

  • Fastest axon = fat diameter and super myelinated

• Diameter size relates inversely to intracellular resistance

Synapse

• Where one neuron passes to another neuron

• Can be in a variety of places: soma, axon hillock, but most commonly:

  • Axodendritric synapse

Presynaptic vs postsynaptic neuron

• Pre-synaptic - The sending neuron

  • Action potential arrives at the axon terminal

  • Voltage-gated Ca²⁺ channels open

  • Ca²⁺ enters the terminal

• Post-synaptic - the receiving neuron

  • Neurotransmitter binds to receptors on dendrites or soma

  • Receptors are usually ligand-gated ion channels

  • Ion flow produces graded potentials:

    • EPSPs (excitatory)

    • IPSPs (inhibitory)

  • These graded potentials determine whether an action potential will fire

Presynaptic to Postsynaptic neuron

2 strategies:

1. Electrical synapses

   1. Current passes from pre to post

   2. Ions can move (current flow) through gap junctions

      1. ***NO NEUROTRANSMITTERS

      2. Don’t create Graded potentials

         1. Transmit signal, don’t generate anything

1. Chemical synapses (more common)

   1. Depolarization (AP) in pre triggers release of chemical neurotransmitters (due to Ca2+ influx), which bind to the post’s neurotransmitter receptors

      1. Receptors are typically ligand-gated channels

   2. Ions can go in/out the post, causing depolarization

      1. *ESSENTIALLY: Electrical → chemical → electrical

      2. Create graded potentials (ESPS / ISPS)

Neurotransmitters exocytosis

• Synaptic versicles release neurotransmitter by exocytosis

  • Neurotransmitter vesicles in pre will fuse with the pre’s membrane, releasing neurotransmitters into the synaptic cleft, which would diffuse towards the post

Exocytosis of Neurotransmitters specific steps

1. Action potential arrives at presynaptic terminal

2. Membrane depolarization opens voltage-gated Ca²⁺ channels

3. Ca²⁺ enters the presynaptic terminal

4. Ca²⁺ triggers vesicle fusion with the presynaptic membrane

   1. Via binding to Synaptotagmin (movement of vesicles), which binds to SNAREs (helps with fusion of vesicles to presynaptic membrane)

5. Vesicles release neurotransmitter via exocytosis

6. Neurotransmitter diffuses across the synaptic cleft

7. Neurotransmitter binds postsynaptic receptors

Calcium voltage channels

• Depolarization in Axon terminal from AP opens Ca2+ voltage gated ion channels

  • These channels are only present at the terminal

• Low amounts of Ca2+ in cells (higher on outside), very high Eq (+130), so very high driving force

  • So when Ca2+ channels open, influx of Ca2+ inside the cell

    • Small amount of huge signaling effect

• Calcium rushes in and binds to protein Synaptotagmin, causing a conformational change in synaptotagmin

  • A protein on vesicle membrane

  • Causes vesicles of neurotransmitters to move towards the membrane

• Synaptotagmin binds to protein SNAREs, helping vesicles and plasma membrane fuse by holding them close together

• Vesicle membranes fuse with presynaptic membrane, and releases neurotransmitter into synaptic cleft

• Neurotransmitters diffuse across cleft, bind to receptors, …