Flashcards in Synaptic Physiology (I,II,III) Deck (56):
Briefly describe the three steps of synaptic transmission
• Action potential in nerve terminal opens extracellular calcium channels
• Calcium entry causes vesicle fusion and transmitter release
• Receptor channels open and Na enters postynaptic cell and vesicles recycle
How big is a typical synapse?
• Really small. The presynaptic nerve terminal ,synaptic cleft and postsynaptic apparatus occupy a volume of about 2 cubic micrometers
What is the calcium sensing protein involved in fusing synaptic vesicles to the presynaptic membrane?
• Calcium binding triggers the fusion of the lipids of the vesicle and surface membranes opening a fusion pore through which NT diffuses out of the vesicle and cell
What is exocytosis?
• The process of a neurotransmitter vesicle fusing with the presynaptic membrane and dumping NT into the synaptic cleft
Where are the places that NT in the synaptic cleft can go after exocytosis?
• Diffusion into the environment
• Active, selective transport back into presynaptic terminal
• Active, selective transport into surrounding glial cells
• Destroyed by enzymatic reaction, particularly with acetylcholine synapses
What is the only NT used at the NMJ?
• NMJ = neuromuscular junction
• Ach = acetylcholine
At the NMJ, does the motor axon have myelin?
• Nope, at the NMJ the motor axon loses its myelin sheath and splays out on a tiny end plate (30um in diameter) on the muscle surface
What is a unique property of the postsynaptic membrane at the NMJ?
• Invaginations of the muscle cell membrane for greater surface area and more sensitivity due to higher density of receptor molecules
What is the Ach receptor?
• A ligand-gated ion channel
• Binding of ach opens the gate and postive charges (sodium mostly) flow into the muscle fiber and depolarize the membrane
• Threshold is reached and voltage gated sodium channels further down will propagate the action potential
What is the resting potential of the muscle fiber?
• Threshold for action potential propagation is -50mV
What happens if not enough ach is released at the NMJ?
• No muscle fiber twitch as threshold is not reached
• Alternatively, if there is too much NT, there is still just one twitch
• All or none
At the NMJ, why can't the presynaptic and postsynaptic membranes be fused and still work?
• The synapse is a super small section of the whole muscle fiber
• The normal nerve axon deploarization would not be enough to bring the muscle fiber membrane to threshold
• You need amplification, which the chemical mediator of the NT and the synapse can provide
How is the chemistry at the synapse the necessary amplifier for threshold to be reached in the postsynaptic membrane?
• Quantal delivery of ach in vesicles
• Thousands of NT molecules per vesicle means there are lots of ligand-gated ion channels being opened for every vesicle that is released
• Amplification due to the number of channels being opened per stimulus
• 1mV per single exocytosed vesicle of NT
When you see the name Katz what do you think of?
• Quantum hypothesis
• Experiments demonstrating it was pre-packaged NT being released at the synapse that sum to reach threshold
*MEPP and single blips
What is meant by MEPP?
• Miniature end plate potential
• Seen by Katz as little 1mV blips at the end plate because of random single vesicle exocytosis (not by calcium but by lipid fusion)
How long does ach bind its postsynaptic membrane receptor and what is the result?
• One milisecond binding time
• 1000 positive charges per milisecond per ach-gated ion channel
• Ends up in one mV change in membrane potential
• Not just sodium because it is a NSC or Non-selective cation channel
What kind of ion channel is the ach receptor?
• NSC (non-selective cation), all cations
• Mostly sodium flows through, but any cation can
How many tansmembrane domains does the ach receptor have?
• 4 transmembrane domains with both N and C termini extracellular
• Transmembrane domains form the pore
How many molecules of ach must bind to open the ach receptor?
• Two ach must bind simultaneously to open this channel
What happens to the calcium ions whose influx triggered vesicle fusion?
• Important clean-up process in the presynaptic terminal
• Calcium pumps, two types
• ATP driven and a Na/Ca exchanger
• 1/10 of a second to clean-up Ca from one action potential
What is the primary method of membrane retrieval for the purpose of recycling vesicles?
• Clathrin-coated or mediated endocytosis
• Clathrin coated pits are pinched off inside the terminal to form coated vesicles
• Dynamin is the active protein that pinches the vesicle off
What is meant by AChE?
• Enzyme that cleaves ach and makes acetate and choline as a byproduct, neither of which can bind the ach gated channel
• This is present in NMJ synaptic cleft as well as in blood, taking care of Ach as it piles up in the cleft or diffuses into blood
What molecule is retrieved by the presynaptic terminal to "recycle" NT at the NMJ?
• Choline is retrieved to make ach again
• Choline must be made by ache in the synaptic cleft
During intense exercise, what keeps the synapse from failing?
• In a healthy person the reputake mechanisms can keep up
• However, if any of the mechanisms replenishing the quantal supply of NT is compromised (disease states) the fidelity of the synapse is not guranteed
• Myasthenia gravis is an example where threshold is not reached, muscle weakness the result
What two things (potentially negative) are happening in a repetetive nerve stimulation in the presynaptic terminal?
• Increase in calcium concentraiton in the terminal
• Releasable vesicles are depleted
What is synaptic facilitaiton?
• Increased calcium level in high frequency stimulation (presynaptic terminal) will result in greater amounts of vesicles fusing per action potential
What is synaptic depression?
• Even though more vesicles would be released in high frequency stimulation (presynaptic terminal) because of faciliation (higher calcium concentration) there is less vesicle material to go around
• Depression is the loss of the pool of readily releasable NT vesicles
Depression and facilitation are happening at the same time. Which one wins?
• Depends on the system of course, or the disease state
• Normally, faciliation happens first with depression later as vesicles are depleted
What is the minimal number of quanta that must be released to reach threshold?
• 30 NT vesicles must be released to reach -50mV and thus threshold
• This is in a normal healthy person
What is happening in myasthenic syndrome?
• Auto-antibodies to calcium channels block calcium influx into the nerve terminal
• Fewer quanta are secreted and sometimes the magic 30 number is not reached, meaning an unfaithful propagation of signal at the NMJ
• Muscle weakness is the clinical result
• Facilitation though can occur at intense activity, thus myathenic syndrome is characterized by INCREASING strength with harder exercise
Why does myasthenia gravis result in profound muscle weakness during exertion?
• Resting quanta release can overcome the reduced number of available ach channels
• In this condition, assume each quanta results in a 0.5mV change, needing 60 quanta release to conduct an action potential
• Synaptic depression during exertion results in that number not being reached
Regarding synaptic faciliation and depression, what is different about CNS and NMJ?
• In a normal person, these processes happen at the NMJ but are clinically irrelevant
• However, CNS transmissions are often sub-threshold and thus these processes play a bigger role and partly determine plasticity
How is a CNS neuron different than a motor unit?
• The motor unit is usually one to one (muscle and nerve are intimately related and simply with one another)
• In the CNS neurons typically receive synaptic inputs from many different neurons (up to 100,000 different ones)
• The "sum" of inputs is much more complex
Why is a CNS synapse considered "weak" when compared with the NMJ?
• There are much fewer releasable quanta at any given time
• There are more inputs, with a smaller number/concentration of receptors on the postsynaptic membrane
While the mechanisms for clean-up in the CNS synapse are the same as those in the NMJ, what is different about them?
• Their relative importance are different
• Most CNS synapses are not cholinergic and thus the ach degradation is not the most important
• Re-uptake actually is the more important mechanism in the CNS synapse
Potassium influx should we associated with what?
• Inhibitory potential
• Moving membrane away from threshold
Sodium influx should be associated with what?
• Excitatory potential
• Moving membrane closer to threshold
What is the CNS major excitatory transmitter?
• Glutamate, opening an NSC channel, which will achieve threshold though not as efficiently as a sodium selective channel
What is the major CNS inhibitor transmitter?
• Increases chloride permeability in postsynaptic membrane
Why can you not just sum up the EPSP and the IPSP?
• It has to do with relative permeabilities of each of the ions in question
• When dealing with chloride, you have to realize that concentration matters as well as potentials
• Everything depends on the relative permeability of the membrane to various ions
What is spatial summation and why is it unique to the CNS synapse?
• Multiple synaptic inputs will summate their released quanta to reach membrane threshold
• The CNS has many more synapses and spatial summation can matter for any circuit. NMJ is more one to one and spatial summation is not a thing so facilitation is the result (temporal in NMJ)
What is temporal summation?
• At the synapse, more quanta are released before the preceding signal decays
What is the main molecular difference between fast synaptic transmission and slow synaptic transmission?
• The type of receptor
• Fast = ligand gated ion channel
• Slow = transmembrane protein that changes conformation and results in longer lasting intracellular changes
What's an example of a first messenger acting as a second messenger?
• Autonomic ganglion cells receive cholinergic synaptic input from CNS
• Ach released like normal and activates ach receptor (like NMJ) which opens NSC channels
• In addition, ach activates a metabotropic receptor present in the postsynaptic membrane which creates a slow EPSP that closes potassium channels, moving the membrane toward depolarization
What NTs work through GPCRs?
• Cathecholamines (epi-nephrine, norepinephrine, dopamine)
• 5-hydroxytryptamine = serotonin
• Enkephalin,vasopressin, nsulin, bombesin, cholecytoskin (peptides)
What is the difference between nicotinic ach receptors and muscarinic?
• Nicotinic = NSC channels, fast synaptic transmission
• Muscarinic = GPCRs, slow synaptic transmission
What do the toxins strychnine and tatanus do?
• Selectively block inhibitory synaptic transmission
• Produce powerful persistent involuntary skelatal muscle contractions
• Seizure or convulsion
What is meant by synaptic integration?
• The summation of excitatory and inhibitory potentials in neurons
Why does the axon hillock start the action potential propagation?
• It has a lower threshold potential, usually because of greater concentration or different poplulation of ion channels
What is meant by associative plasticity?
• Neurons are potentiated not just after their own activity but especially when their own activity is combined with a unique signal from the postsynaptic cell
• Ends up as long term potentiation (LTP) and provides the foundation for memory and learning
What is the molecular key to associative learning?
• NMDA receptor
• Coincidence detector
• Typically the synaps is excitatory and glutamate is NT
• Postsynaptic membrane contains two types of gluatamate receptors, AMPA and NMDA
• AMPA are NSC channels
• NMDA are similar, but they are more permeable to calcium ions than others because their pores have Mg ions in them
What is the "coincidence" that is sensed by the NMDA receptor?
• It must have been bound to glutamate AND have a reverse post-synaptic membrane action potential providing the two forces necessary to eject the Mg ion
• The gluatamate opens the door, the reverse action potential kicks the Mg out of the pore
How does NMDA channel opening result in a stronger synapse?
• Same principle as in pre-synaptic vesicular release
• Calcium influx through NMDA will result in post-synaptic vesicular release
• Instead of NT release, it's AMPA integration into post-synaptic membrane, increasing sensitivity to excitatory stimulus
Besides more AMPA channels posty-synaptically, what else can strengthen a synapse based on NMDA activation?
• NO signaling acts as a retrograde/feedback communication mechanism to strenghten the pre-synaptic release of NT by NMDA activation post-synaptically
How does the pavlov's dog example rely on concidence mechansims like the NMDA receptor?
• Nice try, this is for you to think about