NROB60 S2025 Week 4 Notes: Action Potentials, Types of Synapses, and Chemical Synaptic Transmission

Action Potentials

  • Rapid reversal of the negatively charged resting potential.
  • Membrane becomes positively charged in relation to the outside.
  • Also referred to as spike, nerve impulse, or discharge.
  • Action potentials generated by a patch of membrane are similar in size and duration.
  • They do not diminish as they are conducted down the axon.
  • Electrophysiological recordings of action potentials sound like popcorn popping.

Parts of an Action Potential

  • Resting Potential: The neuron is at its baseline electrical state.
  • Rising Phase: Rapid depolarization of the membrane.
  • Overshoot: The membrane potential becomes positive (above 0 mV).
  • Falling Phase: Repolarization of the membrane back towards the resting potential.
  • Undershoot: The membrane potential briefly dips below the resting potential (hyperpolarization).
  • Graphical representation:
    • Y-axis: Membrane potential (mV), ranging from -80 to 40.
    • X-axis: Time (msec), ranging from 0 to 2.
    • Key points: Resting potential (e.g., -70 mV), threshold, peak of overshoot, undershoot.

Generating Action Potentials

  • Potassium (K+) enters and exits normally through membrane permeability.
  • An event triggers Sodium (Na+) channels to open, depolarizing the membrane.
  • This change prevents K+ influx.
  • If the generator potential reaches the threshold, an action potential is triggered.
  • Electrical current can also trigger an action potential.
  • Action potentials are all-or-none.
  • Continuous electrical current results in multiple action potentials.
  • Maximum frequency is 1000 Hz due to the absolute refractory period (1ms).
  • Relative refractory period: Difficult to initiate another action potential for several seconds after the absolute refractory period.

Flipping the Membrane Potential

  • Once an action potential fires, Na+ channels close, stopping Na+ influx.
  • Potassium (K+) channels open, causing rapid K+ efflux.
  • K+ flows out of the cell until the membrane potential lowers again.

Putting It All Together

  1. Resting State:
    • Activation gates on Na+ and K+ channels are closed.
    • Resting potential is maintained.
  2. Depolarization:
    • A stimulus opens activation gates on some Na+ channels.
    • Na+ influx depolarizes the membrane.
    • If depolarization reaches the threshold, it triggers an action potential.
  3. Rising Phase:
    • Depolarization opens activation gates on most Na+ channels.
    • K+ channels' activation gates remain closed.
    • Na+ influx makes the inside of the membrane positive.
  4. Falling Phase:
    • Inactivation gates on most Na+ channels close, blocking Na+ influx.
    • Activation gates on most K+ channels open, permitting K+ efflux.
    • Efflux makes the inside of the cell negative again.
  5. Undershoot:
    • Both gates of the Na+ channels are closed.
    • Activation gates on some K+ channels are still open.
    • As these K+ gates close and Na+ inactivation gates open, the membrane returns to its resting state.

Action Potential Conduction

  • Axon propagation: Transfer of the action potential down the axon.
  • When Na+ channels open, the influx of positive ions depolarizes the adjacent section of the membrane.
  • Unidirectional due to the refractory period when Na+ channels are inactive.
  • Orthodromic: Soma -> axon.
  • Antidromic: Axon -> soma (backwards propagation).
  • Velocity is approximately 10 m/s.

Factors Influencing Conduction Velocity

  • Speed depends on how far the depolarization ahead of the action potential spreads.
  • This spread depends on:
    • Diameter of the axon.
    • Number of open membrane pores.
  • Narrow axon + many open pores: Most current flows out across the membrane.
  • Wide axon + few open pores: Most current flows down the axon.
  • The farther the current goes, the farther ahead of the action potential the membrane will be depolarized.

Local Anesthesia

  • Temporarily blocks action potentials in axons.
  • Lidocaine is widely used.
  • Binds to the S6 alpha helix of domain IV of the voltage-gated sodium channels.
  • Interferes with the flow of Na+ that normally results from depolarizing the channel.
  • Smaller axons are more affected because a greater proportion of their voltage-gated sodium channels must function to ensure the action potential doesn’t fizzle out.

Myelin and Saltatory Conduction

  • Myelin sheath: Insulates axon to facilitate action potential propagation.
  • Nodes of Ranvier: Where ions cross the membrane to generate action potentials.
  • Distance between nodes is typically 0.2–2.0 mm.
  • Saltatory Conduction: Action potential propagates by skipping from node to node.

Multiple Sclerosis (MS)

  • Demyelinating disease.
  • Immune system attacks axons in the brain, spinal cord, and optic nerves.
  • Lesions form on axon bundles.

Spike-Initiation Zone

  • Part of the neuron where the axon originates from the soma.
  • Typical neurons: Depolarization occurs at the axon hillock caused by input from other neurons.
  • Sensory neurons: Depolarization occurs near nerve endings, caused by sensory input.

Types of Synapses

History of Synaptic Transmission

  • Synaptic Transmission: Passing nerve signals from one neuron to the next at the synapse.
  • Otto Loewi (1921):
    • Showed that electrical stimulation of axons innervating the frog's heart caused a release of chemicals.
    • The chemical was acetylcholine.
  • Bernard Katz:
    • Showed transmission at the synapse of motor neuron and skeletal muscle.
  • John Eccles (1951):
    • Found that most of the brain uses chemical synapses.

Electrical Synapses

  • Allow direct transfer of ionic current from one cell to the next.
  • Gap Junctions: Sites of electrical synapses. Two cells separated by 3 nm.
  • Connexins: Proteins spanning the gap.
  • Connexon: Six connexin subunits together forming the channel.
  • Gap junction channel = 2x connexons.
  • Invertebrates often have electrical synapses between sensory and motor neurons.
  • Gap junctions are usually bidirectional.
  • Electrically coupled: Cells connected by gap junctions.
  • Electrically mediated postsynaptic potential (PSP): Current flow from one neuron into the next.
  • PSPs are usually small (\sim 1 mV) and may not trigger an action potential.
  • Since one neuron is electrically connected with many neurons, several simultaneous PSPs might trigger an action potential.
  • Often found where activity needs to be highly synchronized.
    • E.g., Inferior Olive of the brainstem: Axons connect with the cerebellum to coordinate fine motor control.
    • Deleting connexin36: No change in action potential generation but no synchronization.
  • Also common during development: Helps coordinate brain growth and maturation.

Chemical Synapses

  • Axon terminal (presynaptic element): Contains synaptic vesicles, mitochondria, and active zones.
  • Synaptic cleft: Space between the presynaptic and postsynaptic neurons.
  • Postsynaptic dendrite: Contains receptors and postsynaptic density.
  • Types of CNS Chemical Synapses:
    • Axodendritic: Axon to dendrite.
    • Axosomatic: Axon to soma.
    • Axoaxonic: Axon to axon.
    • Axospinous: Axon to dendritic spine.

Neuromuscular Junction

  • Chemical synapse between axons of motor neurons of the spinal cord and skeletal muscle.
  • An action potential in the motor axon always causes an action potential in the muscle cell it innervates.
  • Reliability and speed are due to:
    • Very large synapse.
    • Presynaptic terminal contains many active zones.
    • Postsynaptic membrane (motor end-plate) contains folds for precise alignment for neurotransmitter receptors.

Chemical Synaptic Transmission

Neurotransmitters (NTs)

  • Speed of Transmission:
    • Glu/GABA/Gly (Amino Acids): Fast (10-100 ms), most CNS synapses.
    • ACh (Amine): Fast, neuromuscular junctions.
    • Slow transmission lasts ms - mins.
  • Amino acids + Amines:
    • Small organic molecules containing nitrogen atoms.
    • Stored in synaptic vesicles.
  • Peptides:
    • Large molecules, chains of amino acids.
    • Stored in secretory granules.

Neurotransmitter Synthesis and Storage

  • Amines:
    • Synthesized in the cytosol.
    • Taken up by vesicles via transporter proteins.
    • Taken to the axon terminal.
  • Peptides:
    • Synthesized in the rough ER.
    • Split in the Golgi apparatus.
    • Secretory granules bud off from the Golgi.
    • Carried to the axon terminal by axoplasmic transport.

Neurotransmitter Release

  • Amino Acids/Amines:
    • Action potential arrives.
    • Depolarization of the terminal membrane causes voltage-gated Ca^{2+} channels in the active zone to open.
    • Ca^{2+} floods the axon terminal and signals NT release (\sim 0.2 ms!).
    • Exocytosis: Vesicles release NTs.
    • Vesicle fuses to the presynaptic membrane.
    • (Ca^{2+})_{in cell} = 0.0002 mM.
    • (Ca^{2+})_{at active zone} = 0.01 mM.
  • Secretory granules: Similar but not at active zones, thus they have higher Ca^{2+} thresholds and require a buildup.
  • Vesicles are thought to be docked at active zones because high Ca^{2+} causes a conformation change, allowing the vesicle to fuse with the cell membrane.
  • This allows NTs to escape into the synaptic cleft.
  • Vesicles are recovered via endocytosis and recycled.
  • There is also a "reserve pool" of vesicles.

Transmitter-Gated Ion Channels

  • Membrane proteins with 4-5 subunits.
  • The pore is usually closed.
  • NT binds => conformational change => pore opens.
  • Fast chemical synaptic transmission.

Generation of EPSPs

  • Excitatory postsynaptic potential (EPSP): Caused by membrane depolarization from NT released by the presynaptic neuron.
  • When the pore is open, ions enter the cell.
  • Low selectivity (e.g., ACh-gated channel is permeable to Na^+/K^+).
  • If the ion enters --> depolarization => excitatory effect.

Generation of IPSPs

  • Inhibitory postsynaptic potential (IPSP): Caused by membrane hyperpolarization from NT released by the presynaptic neuron.
  • When the pore is open, Cl^- enters the cell, bringing the cell further away from the action potential threshold.
  • If the ion enters --> hyperpolarization => inhibitory effect.

G-Protein-Coupled Receptors

  • Metabotropic receptors/G-protein-coupled receptors:
  • Slower, long-lasting.
  • NT binds to the receptor.
  • The receptor activates G-proteins.
  • G-proteins activate effector proteins:
    • G-protein-gated ion channels.
    • Enzymes which synthesize 2nd messengers.
    • Activate additional enzymes in the cytosol.
  • The same NT can have different postsynaptic actions depending on what receptors it binds to!

Autoreceptors

  • NT receptors are found on the presynaptic axon terminal.
  • Usually G-protein-coupled receptors stimulate 2nd messengers.
  • The most common function is to inhibit further NT release.

NT Recovery and Degradation

  • NTs must be cleared from the synaptic cleft via:
    • Diffusion away from synapse.
    • Reuptake by the presynaptic neuron and reloaded into vesicles.
    • Enzymatically destroyed.

Neuropharmacology

  • The study of the effects of drugs on the nervous system.
  • Receptor antagonists:
    • Inhibitors.
    • Bind to the receptors and block (antagonize) the normal action of the transmitter.
    • E.g. Curare.
  • Receptor agonists:
    • Mimic actions of NTs.
    • Cause receptor to function as if a naturally occurring NT bound to it (activates receptor).
    • E.g. Nicotine.