Lecture 4 - Synaptic Transmission I (Electrical & Chemical Synapses)

Active vs Passive Action Potential propagation

Unmyelinated → only active, slower

How to increase the speed of AP propagation?

By increasing the efficiency of passive conduction (charge travels further without decay)

Cable theory

model for studying the passive conduction of electrical signals along a fiber

Rm → insulation of the membrane

Ri → resistance of the cytoplasm to allowing the passing of AP

How to increase the speed of passive conduction along axons?

1. Increasing axon diameter (ex. giant squid axon)

2. Increasing Rm (ex. myelination)

3. Decreasing Ri (already low and constrained by cytoplasm composition)

Nodes of Ranvier

Intermittent regeneration of signal (active conduction)

caspr: prevents sodium channels from migrating away

After NaV depolarizes, the Kv channels repolarize (under myelin to not interfere)

Saltatory conduction

In myelinated cell, AP jumps from one node to the next

Electrical synapses

More common in invertebrates, not just neurons

Fast, synchronous, high threshold (many inputs must integrate → low false positives)

~3 nm gap spanned by gap junctions (tunnels)

Connections: axon-axon, axon-dendrite, dendrite-dendrite

Gap Junctions

6 connexins → 1 connexon (nonspecific, can be ex or in, bidirectional, reliable)

Electrical coupling: pass ions & molecules directly

PSP lower in 2nd cell because not all ions pass through (leaky, Rm)

Common in early development (“fire together, wire together”)

Synchronizes local astrocyte networks → distributed regulatory networks

Otto Loewi - Evidence for chemical neurotransmission

1. Stimulated vagus nerve of frog heart → slowed

2. Transferred fluid to second heart → slowed

3. Some chemical substance transmitted the nerve signal → later found to be ACh

Presynaptic density active zone

protein-dense region on the presynaptic membrane where synaptic vesicles dock, fuse, and release neurotransmitters

Types of neurotransmitters

1. Amino acids

2. Amines

3. Peptides

Neuromuscular junction (NMJ)

Large, accessible, reliable

Motor neuron axon (vesicles packed with ACh) connects to motor end plate (folded membrane with ACh receptors)

Katz’ Hypothesis

1. Applied ACh to NMJ & observed EPPs

2. Saw EPPs that were similar to that obtained from electrical stimulation

3. Applied curare to NMJ (blocks ACh receptors to cause paralysis)

4. No EPP in the presence of curare

Stimulation of presynaptic neuron → generates postsynaptic potential (PSP) → EPP

1. Nerve impulse triggers ACh release

2. ACh binds to ionotrophic receptors on end-plate membrane

3. Sodium channels open → Na+ enter muscle fiber

4. Muscle membrane depolarizes → EEP

5. If strong enough to reach threshold → AP → muscle contraction

Myastenia gravis (MG)

NMJ autoimmune disease - antibodies that attack ACh receptor

ACh blocked, EPPs can’t reach threshold

Symptoms: muscle fatigue, weakness, ptosis (drooping eyelid)

Solution: 1. Rescue AChR, 2. Increase ACh release, 3. Reduce ACh degradation

Neostigmine: slows degradation of ACh by inhibiting acetylcholinesterase

How does AP in motor neuron cause ACh release? Hypothesis: Ca++ influx

Evidence: 

1. Increasing extracellular Ca++ at NMJ leads to larger EPPs

2. Adding Ca++ buffer abolishes EPPs

3. Injection of Ca++ into presynaptic terminal drives EPPs

How are neurotransmitters (like ACh) released?

1. Action potential reaches presynaptic terminal

2. Depolarization causes voltage-gated Ca++ channels to open → influx of Ca++

3. Ca++ binds to synaptotagmin → SNARE complex fuses docked vesicles

4. Exocytosis: neurotransmitters released into synaptic cleft 

5. Receptor binding → enzymatic breakdown (AChE) → vesicle recycling

Difference between EPSP, EPP, mEPP, and AP?

EPSP: Excitatory Postsynaptic Potential, small local depolarization that is graded (size depends on how much NT is released), caused by release of glutamate, decremental, many ESPS must summate to reach AP threshold at Hillock/AIS

EPP: End-Plate Potential, large depolarization at NMJ that is normally enough to reliably exceed the threshold, caused by release of ACh

mEPP: Miniature End-Plate Potential, small spontaneous depolarization at NMJ, random fusion of single vesicles of ACh, used to come up with Quantal Hypothesis

AP: Action Potential, all-or-none, non-decremental

Quantal hypothesis

Neurotransmitters released in discrete packets of uniform size → predicted synaptic vesicles

Confirmed by electron microscopy

1. mEPPs occurred spontaneously 

2. mEPPs got larger after neostigmine treatment (suggesting they are triggered by ACh)

3. Katz reduced extracellular Ca++ → EPPs became very small

4. Discrete amplitudes, multiples of the smallest spontaneous mEPP

Clostridium botulinum

Cleaves SNARES to block vesicle release, flaccid paralysis

Used to treat muscle spasms (cerebral palsy) and cosmetic (Botox)