Week 3 - Synapses and Dendrites (3a–3d)

Electrical and Chemical Synapses: basic structure and function

• Two classes of synapses
  • Electrical synapses
  • Direct electrical coupling between cytosol of two neurons
  • Gap junctions form the electrical connection
  • Computationally inflexible but allow rapid, bidirectional signaling
  • Chemical synapses
  • Transition from electrical signal to chemical signal via neurotransmitter release
  • Slower than electrical synapses but capable of complex processing
• Experimental observation: injected current in presynaptic neuron can leak to extracellular space or transfer to postsynaptic neuron; postsynaptic response depends on synapse type

Electrical synapses (gap junctions): structure and function

• Gap junction structure
  • Gap junction consists of 6 connexin subunits forming a connexon in each cell membrane
  • Two connexons align to make a gap junction channel
  • Channel is non-selective for ions and small molecules
  • Result: direct electrical coupling allowing ions to pass between cells
• Functional implications
  • Electrical PSPs occur rapidly (fast transmission)
  • Because they are direct, they are generally less flexible for computational modulation
  • Postsynaptic response depends on the nature of the electrical coupling
• Diagrammatic note from slides
  • Presynaptic Vm and postsynaptic Vm show tight, fast coupling
  • Electrical PSPs are distinct from chemical PSPs in timing and plasticity

Chemical synapses: basic structure and function

• Key structural features
  • Presynaptic and postsynaptic membranes separated by a cleft of 20–50 nm
  • Presynaptic terminal contains neurotransmitter-filled vesicles (~50 nm diameter)
  • Some neurons contain larger secretory granules (~100 nm)
  • Presynaptic “active zones” host proteins that bind vesicles and mediate release
• Transmission process overview
  1) Neurotransmitter synthesis
  2) Neurotransmitter loading into vesicles
  3) Vesicle fusion and neurotransmitter release
  4) Neurotransmitter binding to post-synaptic receptors
  5) Postsynaptic response (PSP)
  6) Neurotransmitter removal from the synaptic cleft
• Vesicle size and content
  • Vesicles ~50 nm diameter; secretory granules ~100 nm
  • Each vesicle contains a relatively uniform amount of neurotransmitter; minis reflect single-vesicle release

Classification of chemical synapses

• 1) Axon location
  • Axo-dendritic: most common (on dendritic spines or shafts)
  • Axo-somatic: commonly inhibitory
  • Axo-axonic: can modulate a signal before transmission
• 2) Effector target
  • Most axons target other neurons
  • Neuromuscular junction (NMJ): motor neurons to muscle fibers (peripheral synapse)
• 3) Size/strength
  • Number and size of synapses influence strength; simultaneous outputs to multiple neurons vs reliable single output
• 4) Microscopic structure (Gray’s types)
  • Gray’s Type I (excitatory): asymmetric, round vesicles, electron-dense, contact dendritic spines, usually excitatory (e.g., glutamate)
  • Gray’s Type II (inhibitory): symmetrical, oval vesicles, less electron-dense, contact dendritic shaft/body, usually inhibitory (e.g., GABA)
• 5) Neurotransmitter types
  • Amino acids: e.g., Glutamate (cation channels opened), GABA (Cl− channels), Glycine
  • Amines: e.g., Dopamine, Acetylcholine, Histamine
  • Peptides: dynorphin, enkephalins (secretory granules)
• Four criteria for a neurotransmitter
  1) Synthesized in the presynaptic neuron
  2) Defined postsynaptic action after release
  3) Exogenous administration mimics endogenous action
  4) Specific removal mechanism from the synaptic cleft

Neurotransmitter release and receptor action

• Neurotransmitter release steps
  • Synthesis and loading into vesicles
  • Vesicle docking at active zones
  • Ca2+-triggered vesicle fusion and exocytosis (fast)
  • Endocytosis to recycle vesicles
• Vesicle fusion timing
  • Exocytosis can occur within as little as
    $0.2\ \text{ms}$
  • Ca2+ triggers fusion via a network of specialized proteins
• Post-synaptic receptors
  • Ionotropic (ligand-gated ion channels): fast, brief responses
  • Directly gate ion flow; typically less selective than voltage-gated channels
  • Metabotropic (G-protein coupled receptors): slower, longer acting; initiate signaling cascades (e.g., via G-proteins)
  • Metabotropic pathways can modulate ion channels and other cellular processes
• Postsynaptic currents and potentials
  • PSP: transient change in membrane potential due to transmitter-activated channels
  • Excitatory PSP (EPSP): depolarization (e.g., Na+ entry)
  • Inhibitory PSP (IPSP): hyperpolarization (e.g., Cl− entry or K+ exit)
• No explicit y-axis in some PSP plots; focus on direction and relative size of PSPs
• Miniature PSPs (minis)
  • Quanta corresponding to release of a single vesicle
  • PSPs vary in amplitude trial-to-trial; minis represent the basic unit of neurotransmitter release
  • If no vesicles released, a 0 mV response occurs

Neurotransmitter removal and termination of signaling

• Precise timing requires turning off signaling
  • Ca2+ clearance from presynaptic terminal via Na+/Ca2+ exchanger (NCX): 3 Na+ ions move in for each Ca2+ moved out
  • Neurotransmitter removal mechanisms:
  • Diffusion away from synapse
  • Reuptake into presynaptic terminal
  • Enzymatic destruction (e.g., acetylcholinesterase for acetylcholine)

Dendrites, postsynaptic potentials, and summation (3c)

• Why PSPs attenuate by distance
  • Passive conduction along dendrites causes PSPs to decay with distance from the synapse
  • Distance constant concepts:
  • Length constant $\lambda$: distance where the depolarization decays to 1/e of its original size
  • Time constant $\tau$: how quickly the PSP decays over time
• Factors determining decay and spread
  • Dendrite diameter and distribution of ion channels affect $\lambda$ and $\tau$
  • Internal resistance (Ri) and membrane resistance (Rm) influence decay
  • If no voltage-gated channels in dendrite, PSPs decay passively with distance
• Effects of distance on influence at the soma
  • Synapses closer to the soma have a greater impact on spike generation due to attenuation
  • Distal synapses can sometimes have larger local PSPs due to receptor density or local processing, partially offsetting decay
• Trigger zone and spike initiation
  • The trigger zone (axon initial segment / axon hillock) has the highest density of voltage-gated Na+ channels and the lowest spike threshold
  • PSPs must reach this zone to influence firing
• Spatial vs temporal summation
  • Spatial summation: multiple inputs from different locations summate at the soma
  • Temporal summation: inputs arriving in quick succession summate in time
  • Both types depend on membrane time constant and length constant; long constants favor summation and easier reaching threshold

Dendritic computation and active conduction (3d)

• Passive vs active conduction in dendrites
  • Passive conduction: PSPs decay with distance; bidirectional spread; charge leaks through membrane
  • Active conduction: voltage-gated channels in dendrites can boost or propagate depolarizations toward the soma
  • Active conduction is not as reliable as axonal action potentials and does not produce the all-or-none spike, but it supports local computation
• Practical implications for computation
  • Dendrites can perform spatial and temporal integration to influence neuronal output
  • Synaptic location and channel distribution shape the computational capabilities of neurons
• Experimental illustration notes
  • Simultaneous recordings from dendrites and soma show how PSPs propagate and decay; distal inputs can still contribute meaningfully via local amplification

Synaptic plasticity and strength modulation

• Synaptic strength can be modulated by multiple mechanisms
  • Long-term potentiation (LTP): increased synaptic strength via insertion of more receptors into the postsynaptic membrane
  • Structural and functional changes at synapses alter efficacy
  • Example: pre- and postsynaptic receptor density can be redistributed to strengthen or weaken connections
• Vesicle release probability (Pr)
  • Pr is the probability that a vesicle is released in response to an action potential
  • Typical ranges (examples):
  • Spinal cord motor neurons: Pr ∈ [0, 1]
  • Cerebellar climbing fibers: Pr ≈ 0.9
  • Cortical pyramidal cells: Pr ≈ 0.1–0.9
  • Motor neurons: Pr ≈ 1
• Presynaptic modulation of release probability
  • Axo-axonal synapses regulate Ca2+ entry into the presynaptic terminal, modulating vesicle release
  • Mechanisms can be ionotropic (fast) or metabotropic (slower, signaling cascades)
• Paired-pulse facilitation and depression
  • Two stimuli separated by a short interval (e.g., 100 ms) can produce facilitation if Pr is not saturated
  • The second stimulus often triggers greater vesicle release due to residual Ca2+ in the presynaptic terminal, increasing the postsynaptic response
  • If Pr is high, the second response can be smaller (depression) due to vesicle depletion
  • Graphs show two waves of presynaptic Ca2+ influx leading to larger second EPSC and larger postsynaptic response when facilitation occurs
• Autoreceptors and presynaptic receptors
  • Presynaptic metabotropic receptors monitor neurotransmitter release and provide negative feedback
  • Can inhibit neurotransmitter release and synthesis, maintaining homeostasis and preventing overexcitation
• Astrocytes and glial modulation
  • Astrocytes sense neurotransmitters and can regulate synaptic transmission
  • They participate in tripartite synapses, influencing clearance, uptake, and extracellular signaling

Circuits and computation: simple examples

• Simple circuits illustrate how excitatory (A, C, B) and inhibitory (D, I) inputs shape postsynaptic output
• Concepts illustrated
  • Summation (A+B) can cause a downstream neuron to fire if combined input crosses threshold
  • Inhibition (via inhibitory synapses) can subtract or dampen activity
  • Complex circuits can produce oscillations and varied firing patterns depending on connectivity and synaptic strength

Key concepts and takeaways

• Electrical synapses provide fast, direct coupling but limited computational flexibility
• Chemical synapses enable diverse transmission, plasticity, and complex computation
• Synaptic classifications (location, target, size, structure, neurotransmitter) determine functional roles
• Neurotransmitter life cycle: synthesis, loading, release, receptor binding, postsynaptic response, and removal
• Postsynaptic potentials integrate across space and time; dendrites perform substantial computation before reaching the soma
• The trigger zone is critical for translating PSPs into action potentials
• Synaptic strength is modulated by pre- and postsynaptic mechanisms, including release probability, receptor density, neuromodulators, and glial interactions
• Short-term dynamics (paired-pulse) interact with longer-term changes (LTP/LTD) to shape learning and adaptation
• Metabotropic signaling (neuromodulation) can globally adjust excitability by altering ionic conductances and membrane resistance
• Practical implications: understanding NMJ, synaptic plasticity, and dendritic integration is foundational for neural computation and real-world neuroscience applications

Relationships to foundational principles and real-world relevance

• Centered in Bear, Connors, Paradiso chapter on synapses and dendrites (Chapter 5): integrates chemical transmission, postsynaptic potentials, and dendritic processing
• Concepts link to neural coding, learning, and plasticity observed in real neural circuits (e.g., LTP at hippocampal and cortical synapses)
• Ethical, philosophical, and practical implications
  • Modulation of synaptic strength underlies learning, memory, addiction, and neuropsychiatric conditions
  • Understanding synaptic mechanisms informs treatments (e.g., targeting receptor function, synaptic plasticity pathways)

Notation and formulas to remember

• Postsynaptic potentials
  • PSP = EPSP or IPSP depending on ion flow
  • If cation channels open, $V_{m}$ depolarizes (EPSP)
  • If Cl− channels open, $V<em>{m}$ hyperpolarizes toward $E</em>{Cl}$ (IPSP)
• Reversal potentials
  • $E_{Cl} \approx -65\ \text{mV}$ (example from slides)
• Passive dendritic conduction and decay
  • Membrane potential decay with distance: $V(x) = V_{0} e^{-x/\lambda}$
  • Length constant: $\lambda \approx \sqrt{\frac{R<em>{m}}{R</em>{i}}}$ (simplified form) or more detailed for cylindrical dendrites: $\lambda \approx \sqrt{\frac{d\,R<em>{m}}{4R</em>{i}}}$
  • Time constant: $\tau = R<em>{m} C</em>{m}$
• Vesicle release probability (Pr)
  • Release probability is not guaranteed with every action potential: Pr ∈ [0,1]
  • Examples of typical ranges across systems (from slides): spinal motor neurons (0–1), cerebellar climbing fibers (~0.9), cortical pyramidal cells (0.1–0.9), motorneurons (≈1)
• Ca2+-triggered vesicle fusion and exocytosis
  • Ca2+ entry via voltage-gated Ca2+ channels triggers vesicle fusion and neurotransmitter release within ~0.2 ms
• NCX exchanger
  • Na+/Ca2+ exchanger moves 3 Na+ in for every Ca2+ pumped out (net Ca2+ efflux)

Reading reference

• Bear, Connors and Paradiso, Chapter 5 (as assigned) for deeper coverage on synaptic transmission and dendritic processing