Week 4 ELM 9: Synapses

Types of Synapse

Aim

• Transmit signal from one neuron to another.

Terminology

• Post-synaptic potential: EPSP (excitatory post-synaptic potential) or IPSP (inhibitory post-synaptic potential).
• Presynaptic neuron: The neuron sending the signal.
• Postsynaptic neuron: The neuron receiving the signal.
• Synaptic cleft: The space between the pre- and postsynaptic neurons.
• One-way transmission: Rectifying.
• Two-way transmission: Non-rectifying.

Electrical Synapses

• Gap junction: Direct connection between neurons.
• Direct transfer of ions: Allows for rapid communication.
• Non-rectifying: Signal can travel in both directions.
• Fast transmission: Virtually no synaptic delay.
• Signal often attenuated: Signal strength may decrease.
• Connexons: Made up of two connexons.
• Connexins: Each connexon consists of 6 connexins.

Drosophila Giant Fibre System

• Giant fibres: Axons of giant interneurons.
• Electrical synapses: Connect with leg and flight muscle motor neurons for rapid escape responses.

Chemical Synapses

• Synaptic delay: Time taken for the signal to cross the synapse; approximately 0.5 - 2 ms.

Otto Loewi's Experiment (1921)

• Discovery of "Vagusstoff": Demonstrated chemical neurotransmission using frog hearts.
• Experiment: Stimulation of the vagus nerve in one heart, and transfer of the fluid to another heart, showed that a chemical substance (acetylcholine) was responsible for снижающейся heart rate.

Chemical Synapse - Vesicular Release

• Action potential: Arrives at the presynaptic terminal.
• Calcium influx: Voltage-gated Ca^{2+} channels open, allowing calcium to enter the presynaptic terminal.
• Vesicle fusion: Calcium allows vesicles to fuse with the presynaptic membrane and release neurotransmitter.
• Neurotransmitter binding: Neurotransmitter binds to receptors on the postsynaptic cell, causing ion channels to open or close.
• Postsynaptic potential: Excitatory (EPSP) or inhibitory (IPSP) postsynaptic potential is generated.
• Neurotransmitter removal: Neurotransmitter is removed by glial uptake or enzymatic degradation.

EM Morphology of Chemical Synapse

• Presynaptic terminal: Contains synaptic vesicles and mitochondria.
• Postsynaptic cell: Receives the signal.
• Synaptic vesicles: Store neurotransmitters.
• Mitochondria: Provide energy for synaptic transmission.
• Active zone: Region of the presynaptic membrane where vesicles fuse and release neurotransmitter; location of voltage-sensitive calcium channels (VSCC).

Vesicular Release: SNARE Proteins

• SNARE proteins: Synaptobrevin, SNAP-25, and syntaxin.
• Mechanism: SNARE proteins bind to each other, drawing the vesicle close to the membrane.
• Calcium sensing: Intracellular calcium concentrations rise, and calcium is sensed by synaptotagmin, a vesicle protein.
• Fusion: Vesicle fuses with the membrane, releasing neurotransmitter (e.g., ACh) into the synapse.

Quantal Release

• Steps of Synaptic Transmission:
  1. Neurotransmitters are synthesized and stored in vesicles.
  2. Action potential arrives at the presynaptic terminal.
  3. Voltage-gated Ca^{2+} channels open, allowing influx of Ca^{2+}.
  4. Ca^{2+} allows vesicle fusion and neurotransmitter release.
  5. Neurotransmitter binds to receptors, causing channels to open (or close).
  6. Excitatory (or inhibitory) postsynaptic potential is generated.
  7. Neurotransmitter is removed by glial uptake (or enzymatic degradation).
  8. Vesicular membrane is retrieved from the plasma membrane.

Neurotransmitter Release

• Spontaneous Release: Occurs even without calcium.
• Evoked Release: Triggered by calcium influx.
• Quantal Nature: Neurotransmitter release is quantal, meaning it occurs in discrete packets.
• Quantum: Amount of transmitter per vesicle.
• MEPP: Miniature end-plate potential, the postsynaptic response to the release of a single quantum.

Quantal Content

• EPP: End-plate potential
• MEPP: Miniature end-plate potential
• Quantal content: = \frac{EPP}{MEPP}

Miniature Postsynaptic Potentials (“Mini’s”)

• Spontaneous occurrence: Even in zero extracellular Ca^{2+}.
• Amplitude: Multiples of a quantal unit.
• Cause: Release of one or a few quanta (vesicles).
• Effect of lowering extracellular Ca^{2+}: EPSP amplitude decreases in a step-wise manner.
• Quantal analysis: AP-evoked EPSPs involve release of up to 200 quanta per AP.
• Quantal Content: Number of quanta released for one AP.
• Quantum content: Each quantum (packet/vesicle) contains several thousand molecules of ACh.

Vesicle Recycling

• Vesicle Cycle: A series of steps including docking, priming, calcium sensing, fusion, endocytosis, translocation, sorting, loading, storage, and mobilization.

Clathrin and Vesicle Recycling

• Clathrin: Protein involved in vesicle recycling.
• Clathrin coat: Formation of coated pits.
• Constant vesicle size: Helps maintain consistent neurotransmitter release.
• Constant number of vesicles: Ensures a readily available pool of vesicles.
• Constant size of terminal: Maintains structural integrity.

Interactive Figures (Key Proteins)

• Voltage-gated Ca^{2+} channel
• Acetylcholinesterase
• Nicotinic acetylcholine receptor
• SNARE proteins

Toxins Affecting Synaptic Transmission

• ω-agatoxin IVA: From the funnel web spider; blocks P/Q-type voltage-gated calcium channels.
  • Used to subdue prey; helps determine which calcium channels are present in particular synapses.
• Botulinum toxin (Botox): Produced by Clostridium botulinum; cleaves SNARE proteins, stopping neurotransmitter release.
  • Most deadly toxin known; causes muscle weakness and paralysis; used clinically for wrinkles, migraines, muscle spasms, and excessive sweating.
• ω-conotoxin MVIIC: From the magician cone snail; blocks N-type voltage-gated calcium channels.
  • Used to paralyze prey; helps determine which types of voltage-sensitive calcium channels are present in a synapse. Synthetic version (ziconotide) treats pain.
• α-bungarotoxin: From the banded krait; blocks nicotinic acetylcholine receptors.
  • Paralyzes prey; high affinity for the receptor makes it useful for probing the receptor's structure and function.
• Physostigmine (Eserine): From the Calabar bean; inhibits acetylcholinesterase, stopping the breakdown of acetylcholine.
  • Treats myasthenia gravis (MG) by boosting acetylcholine concentrations; can reverse effects of toxins like curare.
• Myasthenia Gravis (MG): Autoimmune disease where nicotinic receptors are attacked by antibodies.
  • Causes muscle weakness and drooping eyelids; treated with acetylcholinesterase inhibitors.