Notes on Synaptic Transmission (Concepts 5.1–5.7)

Concept 5.1: There Are Two Mechanisms of Synaptic Signaling

• Two general classes of synapses in the human brain: electrical synapses and chemical synapses.
• Key upstream (presynaptic) and downstream (postsynaptic) elements differentiate the two classes.
• Electrical synapses
  • Permit direct, passive flow of electrical current from one neuron to another.
  • Current source: potential difference generated by the presynaptic action potential (AP).
  • Signal transmission occurs at gap junctions.
  • Gap junctions contain connexons that form the electrical path between cells.
  • Connexon structure and composition:
  • Connexons are channels formed by six connexin subunits; each connexon is a hemi-channel in pre- and postsynaptic neurons that align to form a pore.
  • Connexins: a family of transmembrane channel proteins; there are 21 human connexin genes (GJA–GJE).
  • Connexins have four transmembrane domains; each connexon comprises six connexins.
  • Pore diameter > 1 nm, larger than many ionic channels, allowing diffusion of ions and larger metabolites.
  • Diffusible content across the pore includes ions and molecules with molecular weights up to several hundred daltons (e.g., ATP, second messengers).
  • Advantages of electrical synapses (distinct minority of synapses):
  • Extremely fast transmission due to virtually instantaneous passive current flow.
    • Example: crayfish electrical synapse shows postsynaptic response within a fraction of a millisecond after presynaptic AP, with little to no delay for signal transmission across the gap.
  • Bidirectional transmission is possible (in most cases), enabling synchronization of electrical activity across populations of neurons.
    • Examples: brainstem rhythm-generation for breathing; synchronized interneuron populations in cortex and thalamus; synchronization among vasopressin- and oxytocin-secreting neurons in hypothalamus.
  • Connexon pores permit diffusion of second messengers, enabling intracellular signaling synchronization across cells (not limited to ions).
  • Relevance to glial networks: gap junctions can synchronize signaling among glial cells.
• Chemical synapses
  • The synaptic cleft is a larger gap between pre- and postsynaptic membranes.
  • Key structural feature: presynaptic synaptic vesicles (membrane-bounded organelles) filled with neurotransmitters.
  • Neurotransmitters act as chemical messengers by binding to specialized postsynaptic receptors.
  • Postsynaptic receptors can trigger ion channel opening/closing, altering postsynaptic conductance and membrane potential.
  • Figures referenced: 5.1C (chemical synapse schematic), 5.4A/B (presynaptic terminal, postsynaptic density, vesicles, active zone, synaptic cleft).
• Core terminologies (VOCAB):
  • Presynaptic: region of transmitter release in the presynaptic neuron.
  • Postsynaptic: region/receptors on the postsynaptic neuron.
  • Connexon: aligned, paired transmembrane channels forming gap junctions between cells; built from connexins.
  • Synaptic cleft: the space separating pre- and postsynaptic neurons at chemical synapses.
  • Synaptic vesicles: vesicles in presynaptic terminals storing transmitter for exocytosis.
  • Neurotransmitters: chemical signals released by presynaptic terminals to transmit information to postsynaptic cells.
  • Connexins: subunits of connexons that form gap junction channels.
  • End plates: specialized postsynaptic regions at neuromuscular junctions.
• Concept connection: Structural differences underpin distinct transmission mechanisms (electrical vs chemical) and their differing speeds, bidirectionality, and diffusion properties.

Concept 5.2: Calcium Ions Regulate the Release of Discrete Packets of Neurotransmitters

• Quantal release of neurotransmitters: neurotransmitter release occurs in discrete packets (quanta).
• Historical anchor: Otto Loewi (1926) demonstrated chemical signaling by showing that electrical stimulation of the vagus nerve releases a chemical signal (acetylcholine, ACh) slowing the heartbeat.
• ACh: a major neurotransmitter at neuromuscular junctions and many central/peripheral synapses; acts at nicotinic (ionotropic) and muscarinic (metabotropic) receptors.
• Neuromuscular junction as a model system (end plates):
  • End plate potential (EPP): large depolarization of the postsynaptic muscle fiber following presynaptic AP, typically triggering a postsynaptic action potential and muscle contraction.
  • A pronounced synaptic delay characterizes chemical synapses compared to electrical synapses.
• Klein and Katz/Fatt observations:
  • Spontaneous miniature end-plate potentials (MEPPs): small, spontaneous depolarizations that resemble EPPs but are much smaller (< 1 mV vs > ~50 mV for EPP).
  • MEPPs are sensitive to ACh receptor blockers (e.g., curare).
  • EPPs and MEPPs show a relationship suggesting unitary transmitter quanta underlie EPPs.
• Quantal hypothesis and statistical support:
  • Incremental increases in EPP amplitude occur in units about the size of single MEPPs, consistent with summated MEPP-like quanta.
  • Poisson statistics predict the distribution of EPP amplitudes if transmitter release is quantal; experimental distributions match this prediction.
  • Conclusion: presynaptic APs trigger synchronous release of many transmitter quanta; each quantum corresponds to a MEPP-like unit.
• Role of Ca2+ in transmitter secretion:
  • Presynaptic APs open voltage-gated Ca2+ channels, causing Ca2+ influx; the steep Ca2+ gradient across the presynaptic membrane (external ≈ $10^{-3} ext{ M}$ vs internal ≈ $10^{-7} ext{ M}$) drives rapid Ca2+ entry.
  • Ca2+ rise in the presynaptic terminal is necessary and sufficient for transmitter release:
  • Direct Ca2+ injection into presynaptic terminals triggers transmitter release without APs.
  • Chelating Ca2+ in presynaptic terminals blocks AP-driven transmitter secretion.
  • The amount of transmitter released is highly Ca2+ dependent; blocking Ca2+ channels inhibits release.
  • Speed of transmitter release varies: ACh release at motor neuron terminals occurs within ~1 ms, whereas neuropeptide release requires high-frequency bursts over seconds.
  • The spatial arrangement of vesicles relative to Ca2+ channels influences local Ca2+ signaling and release kinetics.
• Acetylcholine (ACh) specifics (Table/Box references):
  • ACh receptors: nicotinic (ligand-gated ion channels) and muscarinic (G-protein-coupled receptors).
• Summary relation:
  • Presynaptic APs → Ca2+ influx → Ca2+-dependent vesicle fusion → transmitter release in quanta → postsynaptic response; Ca2+ is essential for triggering release.
• Key formulas (Ca2+ role and relationship to release):
  • Ca2+ driving force and calcium-dependent exocytosis underlie the probability and amount of transmitter release.
  • Notation: [Ca^{2+}]ext ≈ $10^{-3} ext{ M}$; [Ca^{2+}]int ≈ $10^{-7} ext{ M}$; Ca2+ entry triggers vesicle fusion and transmitter exocytosis.

Concept 5.3: A Cycle of Membrane Trafficking is Responsible for Neurotransmitter Release

• Synaptic vesicle localization and content:
  • Synaptic vesicles store neurotransmitters at high concentration (e.g., ACh ~ $100 ext{ mM}$ inside vesicles).
  • A single vesicle typically contains about $10^4$ transmitter molecules, compatible with the amount needed to mimic an MEPP.
• Experimental proof that vesicle fusion causes quantal release:
  • Heuser, Reese, and colleagues correlated vesicle fusion events with quantal content of EPPs at the neuromuscular junction.
  • Varying quantal release pharmacologically (e.g., with 4-aminopyridine, 4-AP) changes the number of quanta released per AP, matching changes in observed vesicle fusion counts.
  • A strong correlation between vesicle fusion events and quanta released supports the view that each fused vesicle yields a single quantum.
• Vesicle recycling and the synaptic vesicle cycle:
  • Exocytosis adds membrane to the presynaptic plasma membrane; this membrane is retrieved by endocytosis and recycled into new vesicles.
  • HRP (horseradish peroxidase) labeling studies reveal endocytosis apparatus: coated vesicles (beginning of endocytosis) → endosomes → reformation into synaptic vesicles.
  • The sequence: coated vesicles → endosome → synaptic vesicles; vesicles re-enter a reserve pool, dock, and prime for subsequent release.
• Time course and efficiency:
  • Whole vesicle cycle time ≈ 1 minute; membrane budding (endocytosis) consumes about $10-20 ext{ s}$; exocytosis is much faster than endocytosis.
  • Local recycling is advantageous due to long distances between soma and presynaptic terminals in neurons; supports sustained neurotransmission during activity.
• Precursors and trafficking:
  • Vesicle components are synthesized in the soma (endoplasmic reticulum and Golgi) and then transported to terminals; local recycling provides rapid replenishment.
• Vocabulary recap:
  • Endocytosis: uptake of material into a cell; at chemical synapses, retrieves vesicle components after exocytosis.
  • Synaptic vesicle cycle: sequence of budding and fusion events maintaining vesicle supply.

Concept 5.5: There are Two Families of Neurotransmitter Receptors

• Receptors convert transmitter binding into postsynaptic signals; two major families differ in transduction mechanisms:
  • Ionotropic (ligand-gated) receptors
  • Contain an intrinsic ion channel; transmitter binding directly opens/closes the channel.
  • Fast postsynaptic responses (milliseconds or less).
  • Examples: ACh receptors at neuromuscular junction; ionotropic receptors at many glutamatergic and GABAergic synapses.
  • Metabotropic (G-protein-coupled) receptors
  • Do not form ion channels themselves; bind transmitter and activate intracellular G-proteins that regulate ion channels or enzymes to generate messengers.
  • Slower, longer-lasting responses (hundreds of milliseconds to minutes or longer).
  • G-proteins serve as transducers linking receptor activation to effector pathways; can directly gate channels or trigger second messenger cascades.
• Key point: Many transmitters can activate both receptor types, providing both fast and slow postsynaptic effects at the same synapse.
• Pharmacological relevance: Metabotropic receptors are major drug targets; about one-third of therapeutic drugs target these receptors.
• Examples of fast vs slow responses:
  • Ionotropic: EPSP/EPP at glutamatergic and GABAergic synapses; neuromuscular junction EPP via ACh receptors.
  • Metabotropic: Slower signaling pathways downstream of G-protein activation, including second messengers that open/close ion channels indirectly.
• Vocabulary recap:
  • Receptor molecules: proteins with extracellular transmitter-binding sites that transduce signals.
  • Ionotropic receptors: ligand-gated ion channel receptors; direct coupling of binding to channel opening.
  • Metabotropic receptors: GPCR-like receptors; activate G-proteins and second messengers to modulate ion channels.
  • G-proteins and G-protein-coupled receptors: seven-transmembrane-domain receptors that trigger intracellular signaling cascades.

Concept 5.6: Postsynaptic Membrane Permeability Changes during the Synaptic Transmission

• When a presynaptic AP triggers transmitter release, thousands of postsynaptic receptors can be activated, producing a macroscopic effect:
  • End plate current (EPC): the postsynaptic current generated by the summed opening of many ligand-gated channels (e.g., ACh receptors).
  • EPC is typically inward, causing postsynaptic depolarization (the end plate potential, EPP).
• Patch-clamp evidence for single-channel conductance:
  • Patch-clamp experiments show that ACh binding to postsynaptic receptors opens ligand-gated ion channels, producing discrete unitary currents in the picoampere range per channel.
  • Single-channel currents demonstrate direct coupling between transmitter binding and channel opening.
• Reversal potential and driving force:
  • The current through ligand-gated channels is governed by the driving force: $I<em>{ ext{EPC}} = g</em>{ ext{ACh}} (V<em>m - E</em>{ ext{rev}})$
  • E_rev is the reversal potential for the EPC, the membrane potential at which there is no net current through the activated channels.
  • For the ACh receptor-activated channels, the reversal potential is near 0 mV, suggesting permeability to multiple cations.
• Ionic contributions to the EPC:
  • If channels were permeable only to Na+, Erev ≈ +70 mV; if only to K+, Erev ≈ -100 mV; if only to Cl−, E_rev ≈ -50 mV.
  • Experimental manipulation shows that ACh-activated channels are permeable to both Na+ and K+, yielding E_rev near 0 mV due to competing fluxes.
  • The actual EPC polarity and magnitude depend on the driving force (Vm − Erev) and the conductance gACh (number of channels opened by ACh).
• Relationship to postsynaptic potential (PSP):
  • The postsynaptic potential depends on the summed effect of many receptor channels opening/closing, not on single-channel events.
  • If Vm is more negative than Erev, IEPC is inward and depolarizing; if Vm is more positive than Erev, IEPC can be outward and hyperpolarizing.
• Practical implications:
  • The reversal potential relative to the resting potential determines whether a synapse is excitatory or inhibitory.
  • The magnitude and polarity of the EPC drive the EPP and subsequent postsynaptic action potentials via activation of voltage-gated Na+ and K+ channels.
  • The same transmitter can produce different PSPs depending on the postsynaptic cell’s ionic gradients and channel expression.
• Key formula:
  • EPC (or IEPC): $I</em>{ ext{EPC}} = g<em>{ ext{ACh}} (V</em>m - E_{ ext{rev}})$
• Consequences for PSPs:
  • The postsynaptic conductance change (increase when channels open; decrease when channels close) is the primary driver of PSPs, which in turn alter the membrane potential toward E_rev for the permeant ions.

Concept 5.7: Postsynaptic Ion Fluxes Determine Whether Synapses are Excitatory or Inhibitory

• PSPs modify the probability of an action potential in the postsynaptic neuron.
  • EPSPs: excitatory postsynaptic potentials; increase likelihood of postsynaptic AP firing.
  • IPSPs: inhibitory postsynaptic potentials; decrease likelihood of postsynaptic AP firing.
• How excitation vs inhibition is determined:
  • The reversal potential (E_rev) of the postsynaptic current relative to the postsynaptic action potential threshold decides whether a PSP is excitatory or inhibitory.
  • The type of ion channel opened by the transmitter receptor and the intracellular/extracellular ion concentrations shape E_rev.
• Example: Glutamatergic synapse (excitatory)
  • Glutamate receptors are typically permeable to Na+ and K+ with E_rev ≈ 0 mV.
  • If resting potential is -60 mV and threshold is -40 mV, a glutamate-induced EPSP depolarizes toward 0 mV, increasing the probability of firing.
• Example: GABAergic synapse (inhibitory)
  • GABA receptors commonly open Cl− channels; for some neurons, E_Cl ≈ -70 mV.
  • If resting potential is -60 mV, E_rev (-70 mV) creates a depolarizing driving force that still results in a hyperpolarizing IPSP; the postsynaptic potential moves away from threshold.
  • If E_Cl ≈ -50 mV instead, opening Cl− channels can produce a depolarizing IPSP, yet inhibition can still occur if the potential remains below the action potential threshold.
• General rule (simplified):
  • EPSP: reversal potential more positive than the action potential threshold.
  • IPSP: reversal potential more negative than threshold.
• Additional nuance: A hyperpolarizing IPSP can occur when E_rev is below the resting potential, but inhibitory effects can also arise from conductance changes that counteract excitatory inputs even if the PSP itself is small or subthreshold.
• Summation and integration:
  • Neurons receive thousands of synaptic inputs; PSPs are often subthreshold individually but can summate in space and time to reach threshold.
  • Spatial summation: multiple distinct synapses active at once.
  • Temporal summation: sequential inputs within short time windows.
  • Inhibitory inputs can shunt or counteract excitatory inputs, shaping the likelihood of AP generation.
• Net outcome: whether a postsynaptic neuron fires depends on the balance of excitation and inhibition at any moment—the summation of EPSPs and IPSPs.
• Practical takeaway: synaptic signaling integrates electrical information via a tug-of-war between excitatory and inhibitory inputs, determining circuit-level information processing.

Summary of core relationships and equations

• Electrical synapses
  • Gap junctions with connexons (assembled from connexins) permit direct ionic/metabolic coupling.
  • Connexon features:
  • 4 transmembrane domains per connexin; 6 connexins per connexon; pore > 1 nm; diffusion of ions and up to several hundred Da.
  • Advantages: fast, bidirectional, synchronization of neuronal and glial networks.
• Chemical synapses
  • Vesicle-mediated transmission across the synaptic cleft; transmitter release via Ca2+-triggered exocytosis; receptor-binding generates postsynaptic conductance changes.
  • Vesicle cycle: docking → fusion (exocytosis) → endocytosis → recycling through coated vesicles and endosomes back to synaptic vesicles; roughly 1 minute cycle time; 10–20 s for budding steps.
  • Vesicle content example: ACh ~ $100 ext{ mM}$; ~$10^4$ molecules per vesicle.
• Calcium and release
  • Presynaptic APs open voltage-gated Ca2+ channels; Ca2+ influx triggers vesicle fusion and transmitter release.
  • Ca2+ concentration gradients drive release; Ca2+ is necessary and sufficient for transmitter secretion.
• Postsynaptic receptors
  • Two major receptor families:
  • Ionotropic (ligand-gated ion channels): fast, direct conductance changes; short-lived responses.
  • Metabotropic (G-protein-coupled receptors): slower, longer-lasting responses via G-proteins and second messengers; therapeutic drug targets.
  • Receptor activation leads to postsynaptic currents and PSPs; the polarity and magnitude depend on ion permeability and driving forces.
• Postsynaptic potentials and their summation
  • EPC: macroscopic postsynaptic current from summed channel openings; reversal potential determines current direction and PSP polarity.
  • PSPs: EPSPs and IPSPs; their reversal potentials relative to spike threshold determine excitation or inhibition.
  • PSPs can summate in space and time to influence neuronal firing; integration shapes neural circuit function.
• Practical/real-world relevance
  • Quantal release concept anchored by studies at the neuromuscular junction; MEPPs and EPPs provide quantitative insight into transmitter release.
  • Metabotropic receptors offer broad pharmacological targets; many therapeutics target G-protein-coupled receptor pathways.
  • Glial gap-junction networks and neuronal signaling add complexity to information processing in the brain.