Synaptic Transmission Notes

Synaptic Transmission

Overview

• Synaptic transmission involves both electrical and chemical synapses.

• This section covers the discovery of chemical synapses, chemical transmission at the motor end-plate, and synaptic integration.

Part 1: The Discovery of Chemical Synapses

• Reticular Theory (Golgi): This theory posited that neurons are physically connected, forming a continuous network.

• Neuron Doctrine (Cajal): This theory proposed that neurons are discrete entities that communicate through specialized contact points.

• Synapses (Sherrington): Points of contact between neurons were termed synapses.

• Basket cell axons terminate in free endings, establishing synapses.

• Otto Loewi's Hypothesis: Nerve stimulation releases a chemical substance that either slows or speeds up the heart rate. Each nerve releases a separate chemical substance with different effects.

Loewi's Experiment (1921)

• Experiment: Stimulation of the vagus nerve in one heart transferred to another heart via shared fluid.

• Conclusion: Vagus nerve stimulation releases a substance called Vagusstoff, which slows the heart rate.

• Vagusstoff was later identified as acetylcholine (ACh) acting through muscarinic receptors.

• This experiment demonstrated that synaptic transmission is chemical.

Electrical Synapses

• Electrical synapses exist throughout the central nervous system (CNS).

• Example: Electrically coupled pair of neocortical inhibitory interneurons (FS-type).

Chemical Synaptic Transmission

• Chemical synapses convert an electrical signal to a chemical signal and back to an electrical signal.

Part 2: Chemical Synaptic Transmission at the Motor End-Plate

Studying Synapses

• The frog neuromuscular junction (NMJ) is a useful preparation for studying synaptic transmission.

  • The NMJ is where a motor neuron communicates with a muscle fiber.

Neuromuscular Junction Structure and Function

• Synapses have electron-dense active zones where neurotransmitter-filled vesicles release their contents into the synaptic cleft.

• Opposite the active zones are specialized areas in the postsynaptic membrane containing neurotransmitter receptors.

• Comparison between NMJ and central synapses.

• Cryo-EM Tomography provides detailed structural information about synapses (Tao et al., 2018). DOI: https://doi.org/10.1523/JNEUROSCI.1548-17.2017

Fatt and Katz Experiments

• Paul Fatt and Bernard Katz's work in the 1950s described the chemical basis of synaptic transmission.

• They used intracellular microelectrodes and curare to study end-plate potentials (EPPs) in isolation.

• Curare, a nicotinic acetylcholine receptor blocker, was used to partially block synaptic transmission.

• Observation: With low-dose curare, end-plate potentials (EPPs) can be resolved, preceding muscle action potentials.

End-Plate Potentials (EPPs)

• After nerve stimulation, a brief current flows into the cell, locally depolarizing the muscle membrane.

• Depolarization spreads along the muscle.

• The spatial and temporal characteristics of the EPP rise and decay are consistent with the muscle's passive electrical properties.

Localized ACh Receptors

• Del Castillo and Katz used iontophoresis of ACh to show that muscle areas near nerve terminals are more receptive to ACh.

• Fluorescently-tagged α-Bungarotoxin can be used to confirm this localization (Sanes and Lichtman).

Ionic Permeability of AChRs

• Fatt and Katz found a decrease in input resistance during an EPP, suggesting the opening of ion channels.

• Takeuchi and Takeuchi, and later Magleby and Stevens, used two-electrode voltage clamp to determine that the reversal potential (Erev) is approximately 0 mV.

Ion Substitution Experiments

• Experiments involving the substitution of ions were used to determine the ionic basis of the EPP.

  • Lowering external chloride ([Cl-]out) showed no effect.

  • Raising external potassium ([K+]out) altered Erev.

  • Lowering external sodium ([Na+]out) altered Erev.

Conclusion of Ion Substitution Experiments

• EPPs are primarily caused by the influx of $Na^+$ and efflux of $K^+$.

Equations Related to Ionic Conductance and Reversal Potential

• Change in Sodium Current: $<br>ΔI<em>{Na} = Δg</em>{Na}(V<em>m - E</em>{Na})<br>$

• Change in Potassium Current: $<br>ΔI<em>{K} = Δg</em>{K}(V<em>m − E</em>{K})<br>$

• At reversal potential Vrev where the net current is zero: $<br>Δg<em>{Na}(V</em>r - E<em>{Na}) = −Δg</em>{K}(V<em>r − E</em>{K})<br>$

• Derivation to determine Vrev:
  $<br>Δg<em>{Na}V</em>r − Δg<em>{Na}E</em>{Na} = −Δg<em>{K}V</em>r + Δg<em>{K} E</em>{K}<br>$
  $<br>Δg<em>{Na}V</em>r + Δg<em>{K}V</em>r = Δg<em>{Na}E</em>{Na} + Δg<em>{K} E</em>{K}<br>$
  $<br>V_r =</p></li></ul><p>\frac{Δg<em>{Na}E</em>{Na} + Δg<em>{K}E</em>{K}}{(Δg<em>{Na} + Δg</em>{K})}<br>$

  • The reversal potential is the weighted average of the equilibrium potentials of the permeant ions.

  • Resting membrane potential equation:
    $<br>V<em>{m</em>{rest}} = 58 ⋅ log <br>\frac{pK [K<em>{Out}]+ pNa[Na</em>{Out}]+ pCl[Cl<em>{in}]}{pK [K</em>{In} ]+ pNa [Na<em>{in }]+ pCl[Cl</em>{out}]} <br>$

  • Membrane potential equation:
    $<br>V<em>m = \frac{g</em>K E<em>K + g</em>{Na}E<em>{Na}}{g</em>K + g_{Na}}<br>$

  • Reversal Potential Equation:
    $<br>E<em>{rev} = \frac{g</em>K E<em>K + g</em>{Na}E<em>{Na}}{g</em>K + g_{Na}}<br>$

  Part 3: Synaptic Integration

  Excitatory Synapses in the CNS

  • The majority of excitatory synapses in the CNS are glutamatergic and mediated by AMPA and NMDA receptors.

  • AMPA and NMDA receptors are permeable to $Na^+$, $K^+$, and $Ca^{++}$.

  • Ionotropic receptors are ion channels.

  • Reversal potential is approximately 0 mV.

  NMDA Receptor Voltage-Dependent Magnesium Block

  • NMDA receptors have a voltage-dependent block by extracellular $Mg^{++}$ ions (Phillip Ascher).

  • Simultaneous activation of multiple AMPAR-containing synapses can remove the $Mg^{++}$ block from NMDARs, resulting in an “NMDAR-spike” (Eyal et al. 2018).

  Fast Synaptic Inhibition

  • Fast synaptic inhibition is mediated by GABA and Glycine receptors, permeable to $Cl^-$.

  • The reversal potential is at $E_{Cl^-}$.

  • Eliminating $Cl^-$ prevents IPSPs (Coombs 1955).

  Excitation and Inhibition

  • Excitation and inhibition are defined by their reversal potential relative to the action potential threshold.

  • Immature neurons can have depolarizing GABA responses (Ben-Ari, 2021).

  Synaptic Summation

  • Most EPSPs are sub-threshold, but they can summate temporally or spatially.

  • The amount of summation depends on the time constants of the postsynaptic response and the length constant of the postsynaptic dendrite.

  • The location of a synapse affects its effectiveness.

  Shunting Inhibition

  • Inhibition can

  Here are some key topics and definitions from the provided note:

  • Synaptic Transmission: The process by which neurons communicate with each other through electrical and chemical synapses.

  • Reticular Theory (Golgi): The theory that neurons are physically connected, forming a continuous network.

  • Neuron Doctrine (Cajal): The theory that neurons are discrete entities communicating through specialized contact points.

  • Synapses (Sherrington): Points of contact between neurons.

  • Otto Loewi's Experiment: Demonstrated that nerve stimulation releases a chemical substance, later identified as acetylcholine (ACh), to affect heart rate, proving chemical synaptic transmission.

  • Electrical Synapses: Synapses that allow direct electrical communication between neurons.

  • Chemical Synaptic Transmission: Conversion of an electrical signal to a chemical signal and back to an electrical signal.

  • Neuromuscular Junction (NMJ): The point where a motor neuron communicates with a muscle fiber, used to study synaptic transmission.

  • End-Plate Potentials (EPPs): Brief currents that depolarize the muscle membrane after nerve stimulation.

  • Localized ACh Receptors: Areas near nerve terminals in muscles that are more receptive to acetylcholine (ACh).

  • Reversal Potential (Erev): The membrane potential at which the direction of ion flow reverses.

  • Glutamatergic Synapses: Excitatory synapses in the CNS mediated by AMPA and NMDA receptors.

  • NMDA Receptor Voltage-Dependent Magnesium Block: NMDA receptors blocked by extracellular $Mg^{++}$ ions, which can be removed by simultaneous activation of AMPAR-containing synapses.

  • Fast Synaptic Inhibition: Mediated by GABA and Glycine receptors, permeable to $Cl^-$.

  • Synaptic Summation: Temporal or spatial summation of EPSPs to reach the threshold for action potential.

  • Shunting Inhibition: A form of inhibition that reduces the size of EPSPs by increasing membrane conductance.