L2 - Chemical Synapses – From Vesicle Loading to Postsynaptic Potentials

Recap of Example Circuits (from previous video)

• Context: four-neuron micro-circuits, each synapse assumed highly reliable; input neuron A fires at a constant, high rate.
• Circuit 1 – Self-Excitatory Loop
  • Neuron C releases glutamate onto itself.
  • Positive feedback → firing rate of C climbs steadily.
  • Rising activity in C drives a parallel increase in downstream neuron B.
  • Illustrates how a single excitatory autapse can generate runaway excitation.
• Circuit 2 – Inhibitory Feedback Loop
  • C excites D; D is inhibitory and projects back to C.
  • Sequence: A ↑ → C ↑ → D ↑ → C suppressed → D suppressed … (cycle repeats).
  • Net result: oscillatory firing in C and therefore rhythmic excitation of B.
  • Demonstrates how adding just one inhibitory synapse converts monotonic input into temporal patterns.

What Makes a Chemical Synapse “Reliable”?

• Two broad domains must succeed on every spike:
  1. Presynaptic transmitter release.
  2. Postsynaptic response.
• Each domain subdivides further:
  • Presynaptic: synthesis → loading → fusion.
  • Postsynaptic: receptor binding → membrane potential change → transmitter removal.
• Any of the six steps can be modulated pharmacologically, developmentally or via learning, giving chemical synapses enormous computational flexibility compared with electrical synapses.

Presynaptic Processes

Neurotransmitter Synthesis

• Small amino-acid transmitters (glutamate, glycine)
  • Endogenously abundant; immediately available in terminals.
  • Only require vesicular transporters for packaging.
• GABA & biogenic amines (dopamine, noradrenaline, etc.)
  • Need specific enzymes for synthesis.
  • Precursors & enzymes synthesized near the nucleus → hitchhike on kinesin along microtubules to the terminal (anterograde transport).
• Neuropeptides / secretory granules
  • Packaged into large dense-core vesicles (secretory granules) in soma.
  • Entire vesicle actively transported to axon terminal before release.

Vesicle Loading & Storage

• Synaptic vesicles = phospholipid spheres, \approx 50\,\text{nm} diameter.
• Each vesicle contains a nearly identical number of transmitter molecules → stereotyped postsynaptic effect (quantum).
• Mitochondria in terminals supply ATP for transporters & pumps.
• Active zone: protein-dense region that tethers vesicles near release sites.

Vesicle Docking, Fusion & Release

• Some vesicles are predocked (partially fused) to minimize delay.
• Action potential arrival → depolarizes terminal → opens voltage-gated \text{Ca}^{2+} channels clustered in active zone.
• Intracellular \text{Ca}^{2+} is normally very low; even small influx triggers:
  • Ca²⁺ binding to sensor proteins (e.g.
    synaptotagmin) → SNARE complex zippering → full fusion (exocytosis).
• Timing: transmitter released within 0.2\,\text{ms} of AP peak (dominant source of synaptic delay).
• After fusion:
  • Endocytosis recycles empty vesicle membrane.
  • Vesicle is re-acidified & refilled for another round.
• Electron-microscopy freeze-fracture sequence
  • Pre-AP: pits showing clustered Ca²⁺ channels.
  • Immediately post-AP: “Ω-profiles” of fused vesicles dumping content.
  • Later: membrane invaginations marking endocytosis pits.

Postsynaptic Processes

Receptor Types

• Ionotropic (ligand-gated ion channels)
  • Transmitter binds → pore opens directly.
  • Latency: micro-seconds; duration limited by ligand dissociation.
  • Usually non-selective cation channels for glutamate (Na⁺ in > K⁺ out).
  • GABA$_A$ & glycine receptors = Cl⁻ ionotropic channels.
• Metabotropic (G-protein-coupled receptors, GPCRs)
  • Transmitter binds → activates membrane-anchored G protein.
  • G protein can: open/close ion channels, modulate enzymes, alter gene expression.
  • Slower onset, longer lasting, spatially diffuse.

Postsynaptic Potentials (PSPs)

• EPSP (excitatory): depolarizing change that raises AP probability.
• IPSP (inhibitory): hyperpolarizing or shunting change that lowers AP probability.
• Amplitude depends on:
  • Number of vesicles released / receptors activated.
  • Driving force & channel conductance.
• Example mechanics:
  • Glutamate → opens non-selective cation channels.
  • Na⁺ influx dominates because E_Na (~+60\,\text{mV}) is far from rest; K⁺ efflux is smaller driver.
  • GABA → opens Cl⁻ channels.
  • E_Cl \approx -65\,\text{mV} (≈ RMP) ⇒ little net voltage change, but increased Cl⁻ conductance “clamps” membrane → shunting inhibition.

Modulation via Metabotropic Cascades (Example)

• Noradrenaline binds β-adrenergic GPCR → activates G_s.
• G_s → stimulates adenylyl cyclase → converts ATP to \text{cAMP}.
• cAMP → activates protein kinase A → phosphorylates & closes K⁺ channels.
• Consequences:
  • Fewer open K⁺ channels → higher membrane resistance R_m.
  • Given same synaptic current, \Delta V = I \times R_m increases ⇒ neuron becomes more excitable.
  • Single transmitter molecule can influence many nearby channels (signal amplification).

Termination of Synaptic Transmission

Presynaptic \text{Ca}^{2+} Clearance

• Na⁺/Ca²⁺ exchanger (NCX): 3\,\text{Na}^+{out} + 1\,\text{Ca}^{2+}{in} \rightarrow 3\,\text{Na}^+{in} + 1\,\text{Ca}^{2+}{out}.
• Powered indirectly by Na⁺ gradient maintained by Na⁺/K⁺-ATPase.
• Keeps resting cytosolic Ca²⁺ at nanomolar levels; stops spontaneous vesicle fusion.

Neurotransmitter Clearance from the Cleft

1. Diffusion away from receptor field.
2. Reuptake via transporters into:
   • Presynaptic terminal (recycling).
   • Perisynaptic astrocytes (especially for glutamate).
3. Enzymatic degradation
   • Classic example: acetylcholine → acetyl + choline by acetylcholinesterase at neuromuscular junction.

Integration & Summation (Preview)

• Whether an EPSP reaches AP threshold depends on:
  • Amplitude of individual EPSP.
  • Spatial summation: multiple inputs at different synapses fired simultaneously.
  • Temporal summation: rapid succession of EPSPs at one synapse.
• If summed depolarization crosses voltage-gated Na⁺ channel threshold → AP fires.
• Upcoming sessions will combine EPSPs & IPSPs to explore dendritic computation.

Key Numerical / Temporal Reference List

• Vesicle diameter ≈ 50\,\text{nm}.
• Synaptic delay dominated by exocytosis ≈ 0.2\,\text{ms}.
• Intracellular resting [\text{Ca}^{2+}] ~ 100\,\text{nM} (vs extracellular mM range).
• E_Cl and typical RMP ≈ -65\,\text{mV}.
• NCX stoichiometry: 3:!1 (Na⁺:Ca²⁺).
• Driving forces: ENa ≈ +60\,\text{mV}; EK ≈ -90\,\text{mV}.

Ethical & Practical Implications

• Each molecular step can be a drug target (e.g.
  • SSRIs blocking serotonin reuptake.
  • Botulinum toxin cleaving SNARE proteins → stops vesicle fusion.)
• Plastic modulation of synthesis, receptor density, or reuptake underlies learning, addiction, and many neurological disorders.
• Understanding timing & reliability is essential for designing neural-prosthetic interfaces and treating synaptic pathologies.