• Neuronal Structure ( important for synaptic transmission ) :

  • Axon

    • Axon initial segment

  • Presynaptic terminal/bouton

    • synaptic vesicles

    • mitochondria

    • active zones

  • Synaptic cleft

    • Postsynaptic cell ( dendrite )

  • receptors signaling molecules scaffolding molecules

• the heart does calcium-induced-calcium-release , skeletal muscle uses direct contact of ryanodine receptors instead

• Adding myelin increases resistance ( membrane )

  • increasing resistance increases conduction velocity

• Adding myelin decreases capacitance

  • decreasing capacitance decreases time constant

    • cell is quicker to charge / discharge

• Adding myelin increases Conduction Velocity :

  • Axon Diameter :

    • Larger axons have lower axial resistance ( Ri ) , allowing current to spread more easily down the axon

    • Conduction velocity = √(axon diameter) for unmyelinated axons

      • and more linearly proportional to changes in diameter for myelinated axons

  • Myelin Thickness :

    • Thicker myelin → faster conduction, up to an optimal point.

    • Myelin increases membrane resistance (Rm) and decreases membrane capacitance (Cm):

      • High Rm: Prevents leak of ions.

      • Low Cm: Faster charging of the membrane (shorter time constant τ = Rm × Cm).

    • Together, this allows action potentials to jump faster (saltatory conduction) between nodes

    • "g-ratio" matters:

      • g-ratio = inner axon diameter / outer fiber diameter (including myelin).

      • Optimal g-ratio ≈ 0.6–0.7.

        • Too little myelin = poor insulation.

        • Too much myelin = slows it down by increasing internodal capacitance.

  • Internodal Length ( Distance between nodes of Ranvier )

    • Longer internodes → faster conduction ( to a limit )

    • Fewer nodes = fewer sites where the AP needs to regenerate, saving time.

    • But if internodes are too long, signal may fail to reach the next node (passive depolarization too small).

    • Optimal internodal length depends on axon size — typically ~100 times the axon diameter.

• Axon diameter and myelin thickness increase during development

• Internodal length increases during development

• Where is the site of action potential initiation?

  • axon initial segment

• Ion channels are uniformly distributed along the unmyelinated axons

  • High density of Na + channels at the axon initial segment

  • Diffuse and lower concentration of Na + channels along the distal unmyelinated axons

• Ion channels are highly accumulated at the AIS and nodes along myelinated axons

  • High density of Na + channels at the axon initial segment and nodes of Ranvier

  • No or little Na + channels in internodal segments

• Propagation :

  • In unmyelinated axons, action potential propagation is continuous along the length of the axons.

  • In myelinated axons, action potential propagation is saltatory: the action potential jumps from node to node.

  • Myelin decreases capacitance and increases resistance, both contributing to saltatory conduction.

• Demyelination leads to conduction slowing / block

  • Decreases membrane resistance (Rm) ➔ more current leaks out of the axon.

  • Increases membrane capacitance (Cm) ➔ slower membrane charging, so the axon can't depolarize quickly.

  • Slows conduction velocity dramatically because passive spread of depolarization is weakened.

• K + channel blocker restores conduction in experimentally demyelinated nerves

• Lysolecithin = artificial demyelination

• Acute Inflammatory Demyelinating Polyradiculoneuropathy ( AIDP )

  • autoimmune attack demyelination on PNS nerves

  • Guillain-Barre type

• Multiple Sclerosis ( MS ) :

  • autoimmune attack on oligodendrocytes ( CNS )

    • loss of myelin

  • disrupted paranodal and nodal organization

  • treatment = K+ channel blocker

• Myasthenia Gravis ( MG ) :

  • autoimmune attack on skeletal muscle neuromuscular junction ACh receptors

  • treatment = acytlecholine esterase inhibitors

    • but the balance is tricky , because too much inhibitor will cause too much available acetylcholine

      • then the receptors will naturally become desensitized on their own due to excess ACh

• If you voltage clamp some muscle fiber at -90 mV vs clamping it at -20 mV ,

  • the one clamped at -90 will have a much larger current measured

    • there is a larger driving force for acetylcholine

• Cardiac Action Potential

Figure 1. CICR, SOICR, and triggered arrhythmia. Left (in blue) depicts the mechanism of CICR, in which an action potential activates the voltage-dependent L-type Ca2+ channel, leading to a small Ca2+ influx. This Ca2+ entry opens the RyR2 channel in the SR, resulting in SR Ca2+ release and muscle contraction. Right (in red) denotes the mechanism of SOICR, in which spontaneous SR Ca2+ release or Ca2+ spillover occurs under conditions of SR Ca2+ overload caused, for example, by stress via the β-adrenergic receptor (b-AR)/PKA/phospholamban (PLB) signaling pathway. SOICR can activate the NCX, which, in turn, can lead to DADs and triggered activities.

• Dopamine for example can bind to both stimulatory and inhibitory GPCRs

• Extracellular magnesium is used to block / inactivate NMDA channels at negative potentials

• Heuser Paper :

  • Hypothesis = synaptic vesicle exocytosis underlies quantal neurotransmitter release

    • one synaptic vesicle fusing with the membrane corresponds to one quantum of neurotransmitter release,

      • and these events occur independently at the presynaptic active zone

  • Conclusions :

    • Each vesicle undergoing exocytosis corresponds to a quantum of neurotransmitter release

    • Vesicle fusion events are independent, not cooperative

    • Quick-freezing successfully captures exocytosis events.

    • 6At low levels of release, collapsed vesicles must be included to match quantal output

  • Evidence :

    • Freeze-fracture electron microscopy captured vesicles fusing with the membrane 5–6 ms after nerve stimulation, matching the timing of neurotransmitter release.

    • 4-aminopyridine (4-AP) was used to increase quantal output, showing a dose-dependent increase in vesicle exocytosis events.

    • Quantitative correlation: The number of vesicles fusing matched the number of quanta released, across low to high 4-AP concentrations.

    • Spatial analysis showed vesicle openings occur precisely at active zones, not elsewhere, and are randomly distributed, supporting independent vesicle fusion.

    • At lower 4-AP doses, inclusion of collapsed vesicles (early fusion stages) improved correlation with physiological data.

    • No evidence for synchronized or cooperative fusion — each vesicle acts independently.

  • Together, this evidence strongly supports the hypothesis that synaptic vesicles fuse with the membrane to release neurotransmitter quanta, and that this can be directly visualized and quantified using high-resolution, time-locked quick-freezing techniques.

• How to calculate $m$$m$ using method of failures :

  $$m=ln\left(\frac{\mathrm{\#}trials}{\mathrm{\#}failures}\right)$$

• Compare and Contrast synaptotagmin vs synaptobrevin knockouts