NeuroSciense 2

  1. Synaptic Transmission 
    The chemical and electrical processes by which the information encoded by action potentials is passed on at synaptic contacts to a target cell is called synaptic transmission

    Chemical synapses is the most abundant type of synapse in the nervous system. 
  2. Electrical synapses
    Cytoplasmatic continuum 

    Gap Junction

    Gap junction channels 
  3. Chemical Synapses
    No cytoplasmatic continuum 

    Synaptic vesicles 

    Synaptic vesicle fusing 

    Postsynaptic neurotransmitter receptor
  4. Otto Loewi's Frog Heart Experiments 
    In 1903 Otto Loewi wondered why one of the heart nerves (the accelerator) speeds up the heart and the other (the vagus) slows it down, even though the electrical pulses of the nerves were nearly identical. 

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  5. Otto Loewi's Frog Heart Experiments 

    The Hypothesis
    Loewi suggested that the two nerves released different chemicals at their terminals when stimulated. The vagus chemical would slow down the heart and the accelerator chemical would speed it up. 
  6. Otto Loewi's Frog Heart Experiments

    The Experimental Test
    Hearts, with their nerves intact, were dissected from two frogs. 

    The hearts were hooked up to mechanical devices which recorded their heart beats. 

    Then the vagus nerve of one heart (the donor) was electrically stimulated. 

    The donor heart immediately slowed down, as expected. 

    A sample of the fluid passing through the donor heart was taken with a small pipette and this fluid was dripped onto the second heart (the recipient). 

    The recipient heart slowed down, even though its vagus had not been stimulated. Chemicals released by the donor heart into the fluid were sufficient to produce slowing.

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  7. End Plate Potential (EPP)
    End plate potentials (EPPs) are the depolarizations of skeletal muscle fibers caused by neurotransmitters binding to the postsynaptic membrane in the neuromuscular junction.

    They are called "end plates" because the postsynaptic terminals of muscle fibers have a large, saucer-like appearance.

    When an action potential reaches the axon terminal of a motor neuron, vesicles carrying neurotransmitters (mostly acetylcholine) are exocytosed and the contents are released into the neuromuscular junction. These neurotransmitters bind to receptors on the postsynaptic membrane and lead to its depolarization. In the absence of an action potential, acetylcholine vesicles spontaneously leak into the neuromuscular junction and cause very small depolarizations in the postsynaptic membrane. This small response (~0.5mV) is called a miniature end plate potential (MEPP) and is generated by one acetylcholine containing vesicle. It represents the smallest possible depolarization which can be induced in a muscle.
  8. End Plate Potential (EPP) 

    Miniature End Plate Potential (MEPP) 
    An action potential in the presynaptic motorneuron can cause a transient depolarization of the post synaptic muscle fiber. This change in membrane potential, called an end plate potential (EPP) is normally large enough to bring the membrane potential of the muscle cell well above the threshold for producing a postsynaptic action potential. The post synaptic action potential triggered by the EPP causes the muscle fiber to contract. 
  9. The discovery of miniature end plate potentials
    Sir Bernard Katz 

    The break through of katz's experiment: spontaneous changes in muscle cell membrane potential occur even in the absence of stimulation of the presynaptic motor neuron. These changes have the same shape as EPPs but are much smaller. 

    Release of acetylcholine does occur in discrete packets, each equivalent to a MEEP. 
  10. The amplitude of the EPP fluctuates 
    Smallest EPP not smaller than a mini. 

    Increments in amplitude occurs in units or "quanta" 

    One quanta is the smallest unit of transmitter release. 

    The increments have the size of a mini. 

    One miniature EPP correspond to the release of one vesicle.

    AP synchronize vesicular release.
  11. Transmitter release can be described with binomial statistics
    Px= [n! /(n-x)!x!] * [pxqn-x]:

    n: number of release sites (only one vesicle (quantum) can be released for each release site)

    p: probability of releasing one vesicle (assumed to be the same at each release site)

    q = 1-p ; i.e. the probability of not releasing a vesicle

    Px: probability of releasing x vesicles

    Transmitter release can be described with binomial statistics. For large n and low p (e.g. low external [Ca2+]) transmitter release can be described by a Poisson distribution:

    P= (mxe-m) / x!

    m = p*n ; i.e. average number of quanta released over all trials
  12. Vesicular Cycling
    The classic three-pool model. 

    1. The reserve pool makes up ~80-90% of the total pool

    2. The recycling pool is significantly smaller (~10-15%). 

    3. The readily releasable pool (RRP) consists of a few vesicles. 
  13. Two Ways to Release Neurotransmitter
    Kiss and Run 

    Full fusion 

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  14. Vesicular Cycling Kinetics
    • Exocytosis 
    • Endosome --> Budding --> Docking --> 

    •                                    Endocytosis
    • Priming --> Fusion --> Budding --> Endosome
  15. What is the relationship between Ca2+and transmitter release?
    Highly nonlinear relationship: EPP = k[Ca2+]4
  16. Neurotransmitter release
    When the action potential arrives at the synaptic terminal, the resulting depolarization results in the activation of voltage-gated Ca2+ channels.

    Ca2+ enters the terminal, according to its electrochemical gradient. The amount of Ca2+ that enters the terminal is extremely dependent upon the amplitude and shape of the action potential. Short duration APs spend less time above the voltage threshold for activation of voltage-gated Ca2+ channels, resulting in the opening of fewer channels, and less Ca2+ entry. 

    Ca2+ entry triggers a conformational change in specific proteins in docked synaptic vesicles that results in fusion of the vesicle to the plasma membrane. 

    Vesicle fusion causes the neurotransmitters contained in the vesicle to spill out into the synaptic cleft, where they can diffuse toward the receptors on the postsynaptic cell.

    At the synapse, vesicle fusion is a tightly regulated process, compared with the constitutively active membrane-recycling processes that are involved in protein trafficking through the endoplasmic reticulum/Golgi apparatus or cell division.

    Compared with the other steps occurring at a chemical synapse, vesicle fusion is extremely fast.
  17. Which Ca2+channel is responsible for Transmitter release?
    ωconotoxin MVII A :Blocks N-type Ca2+ channels

    ω Agatoxin IVa: Blocks P-type Ca2+ channels
  18. N-Type Ca2+Channel
    Channel name:  CaV2.2

    Conductance: 20pS

    Activation Va = +7.8mV

    Blockers: conotoxin GVIA

    Channel distribution: neurones (presynaptic terminals, dendrites, cell bodies)
  19. P-Type Ca2+ Channel
    Channel name: CaV2.1

    Conductance: 9, 14, 19pS

    Gating inhibitors: -agatoxin IVA

    Channel distribution: neurones (presynaptic terminals, dendrites, some cell bodies)
  20. Removal of Transmitter From the Synaptic Cleft
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    Acetylcholine + water--> Choline + Acetate 

    The enzyme used is Acetylcholinesterase
  21. Substances that Block Acetylcholinesterase
    Physostigmine (eserine)

    Nerve Gas (Sarin)
  22. Criteria that Define a Neurotransmitter Substance
    Present in Presynaptic Neuron Activity

    Dependent Release

    Postsynaptic Receptors for Neurotransmitter
  23. How do Vesicles Interact with the Presynaptic Membrane

    • The SNAREs: Syntaxin
    •                  : synaptobrevin 
    •                  : SNAP-25
  24. The SNARE Complex

    (a stable four helix bundle)
    High stabilization energy of the bundle;3-17 complexes. Sufficient energy for fusion

    Synaptotagmin: a Ca2+ binding vesicular protein
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NeuroSciense 2