synaptic transmission 1-3 Flashcards
- Brush up on the mechanism of the action potential and the Nernst equation.
E= 2.303 (RT/zF) log 10 [ion outside cell]/[ion inside cell]
- What is electrical synaptic transmission?
Rare! Synchronizes cells that need to fire together (like
motor neurons in the respiratory center). Gap junctions connect cytoplams of neurons and allow ions to flow (connexin channels on one cell meet up with connexin on the other cell). Rare! Synchronizes cells that need to fire together (like
motor neurons in the respiratory center). Gap junctions connect cytoplams of neurons and allow ions to flow (connexin channels on one cell meet up with connexin on the other cell). Rare! Synchronizes cells that need to fire together (like
motor neurons in the respiratory center). Gap junctions connect cytoplams of neurons and allow ions to flow (connexin channels on one cell meet up with connexin on the other cell). Rare! Synchronizes cells that need to fire together (like
motor neurons in the respiratory center). Gap junctions connect cytoplams of neurons and allow ions to flow (connexin channels on one cell meet up with connexin on the other cell).
Name a limitation of electrical synaptic transmission (compared to chemical transmission). Why would it be ineffective at the neuromuscular junction?
In order to provide enough current to depolarize the postsynaptic cell to threshold the presynaptic terminal has to be comparable in size to the postsynaptic cell. Can only be excitatory, signal cant be amplified, integration of signals is difficult, cant modulate signal
Advantages of electrical synaptic transmission
Fast, simple, bidirectional, easy to trigger synchronous activity, delay is virtually absent
Is electrical synaptic transmission important in the mammalian CNS?
Rare in mammals- more common in lower vertebrates and invertebrates
Name examples of electrical synaptic transmission.
Non-nervous tissue: heart muscle, smooth muscle, embryonic cells, epithelial cells. Escape reflexes. Retina, inner ear
Name a disease that results from electrical synapse deficiency
Charcot-Marie-Tooth X neuropathy (point mutation in connexin-32)
Tonabersat
modulates gap junction
What attaches presynaptic vesicles to the pre-synaptic membrane?
SNARES: syntaxin, synaptobrevin, and SNAP-25
Describe the actions of snares
Exocytosis: The vesicle-snare (v-snare) and the target-snare (t-snares) latch on to each other and bring the membranes close together.Calcium triggers the fusion of the two membranes. NSF then binds to the coiled up snares and unwinds them with help of ATP. The cell endocytoses only the v-snares, and leave the t-snares in the surface membrane.
Which snares are v-snares, and which are t-snares
Synaptobrevin is a V snare. SNAP-25 and syntaxin are t-snares.
Where do clostridia toxins act
Botulinum cleaves snare proteins at different locations, blocking exocytosis. When the diaphragm is paralyzed victims suffocate. Tetanus toxin also cleaves snare proteins but preferentially affects inhibitory synapses.
- Name the presynaptic events involved in transmitter release, from the time of the arrival of an action potential to exocytosis.
AP at presynaptic terminal > depolarization > VG Ca channels open > Ca flows into cell > Ca binds synaptotagmin (SNARE Ca sensor) > fusion of vesicle with cell membrane > fusion pore > exocytosis of neurotransmitter
Describe the subsequent presynaptic events involved in cleanup operations, both outside the cell (consider the neurotransmitter molecules) and inside the cell (consider sodium ions, calcium ions, synaptic vesicles, and neurotransmitter).
Outside: Neurotransmitter disappears from cleft by diffusing out, being recycled into presynaptic terminal, or being destroyed by enzymes (esterases). Inside: vesicle membrane is internalized and refilled, neurotransmitter is synthesized by enzymes in nerve terminal cytoplasm then pumped by Na-coupled transporters into vesicle, Ca removed via Ca-Na antiporter or primary active transport, Na removed, K reabsorbed
Types of vesicle recycling
Kiss and run exocytosis: After a single action potential, vesicle membrane is recaptured within about one second, probably close to the site of exocytosis. More intense stimulation: vesicles collapse into the surface,flowing to adjacent sites specialized for endocytosis. Really intense stimulation: surface membrane ‘bubbles’ back inside as long, narrow infoldings and complete recycling may take several minutes.
- How does tetanus toxin act
Tetanospasmin is encoded on a plasmid. It is produced by growing cells, released during cell lysis. Binds to peripheral nerve terminals, transported to CNS where it becomes fixed to gangliosides at the presynaptic inhibitory motor nerve endings, and taken into the axon. It blocks the release of inhibitory neurotransmitters (glycine and gamma-amino butyric acid) across the synaptic cleft by cleaving synaptobrevin II, a component of synaptic vesicles.
how does botulinum toxin act?
Type A is most common in US. Absorbed by upper GI, passes into blood, reaches peripheral neuromuscular synapses and binds to the presynaptic stimulatory terminals and blocks the release of the neurotransmitter
acetylcholine (by cleaving SNARES) which is required for a nerve to simulate the muscle.. Type A is most common in US. Absorbed by upper GI, passes into blood, reaches peripheral neuromuscular synapses and binds to the presynaptic stimulatory terminals and blocks the release of the neurotransmitter
acetylcholine (by cleaving SNARES) which is required for a nerve to simulate the muscle.. Type A is most common in US. Absorbed by upper GI, passes into blood, reaches peripheral neuromuscular synapses and binds to the presynaptic stimulatory terminals and blocks the release of the neurotransmitter
acetylcholine (by cleaving SNARES) which is required for a nerve to simulate the muscle..
Infection vs intoxication with botulism
Infection only occurs in infants where the botulinum organisms can grow in the bowel of infants lacking competing intestinal bacteria. In adults, the illness is more of an intoxication from the toxins alone
- Name the postsynaptic events involved in synaptic transmission.
Neurotransmitter binds receptors > response can be excitatory or inhibitory, have an onset that is fast or slow, cause a membrane potential change that is brief or persistent
Myasthenic syndrome
Immune system makes antibodies against pre-synaptic Ca channels in neuromuscular junction, blocking Ca influx and leading to fewer quanta secreted. This causes weakness. Aka lambert eaton
Which neurotransmitters are most common at neuromuscular junction? In CNS?
NMJ: acetylcholine. CNS: glutamate (excitatory), glycine (inhibitory), GABA (inhibitory)
What other compounds can bind to the GABA receptor?
ethanol, benzodiazepine, barbiturates, neurosteroids
How is GABA removed from the synapse
reuptake by glial cells and the pre synaptic terminal.
What are GABA reuptake inhibitors used for
seizures, epilepsy, convulsions, anxiety, as anesthesia (prevents GABA from being taken up by glia cells, so it continues to stimulate the post synaptic terminal)
Compare/contrast NMJ and CNS synapses in relation to speed, excitatory/inhibitory, strength, neurotransmitter, intelligence
NMJ: Fast, excitatory, strong, Ach, stupid, large. CNS: Fast and slow, excitatory and inhibitory, weak, Ach+ glutamate + GABA, smart
- What is the ‘job description’ for a motor nerve terminal?
every time an action potential arrives from the CNS, it must secrete enough ACh to depolarize the muscle fiber by 30mV to threshold for an action potential. Too little Ach- no AP. Too much Ach- still just one twitch (all or none)
- Describe how the neuromuscular synapse amplifies the incoming signal in order to depolarize the muscle fiber to threshold for an action potential.
Each vesicle released from presynaptic neuron depolarizes the muscle about 1mV, so up to 100 vesicles are released during each AP, amplifying the signal.
Types of ion channels in muscle involved in Aps
Ligand gated channels first bind to Ach and allow any cation (non-selective cation channel) to go into the cells at that site (small area). Then, voltage gated channels open when threshold is reached and specifically let Na into the cell to continue the AP
- What is the safety factor at the neuromuscular junction?
Safety factor is a measure of the excess neurotransmitter released which is over that amount needed for an AP. This ensures that AP’s are still conducted during repetitive stimulation when number of vesicles declines.
Do CNS synapses have safety factors as well? Why / why not?
usually not- the signals are mostly too weak to stimulate an AP on its own
Define miniature end plate potentials
MEPP reflects the spontaneous exocytosis of a single synaptic vesicle resulting in a depolarization of about 1mV
Quantum hypothesis and vesicular hypothesis
quantum hypothesis: neurotransmitter secretion occurs by way of an integral number of multimolecular packets. vesicular hypothesis: each quantum reflects the contents of a single synaptic vesicle.
Structure of Ach gated channel
Contains 5 subunits (2 alpha), with each subunit weaving back and forth across membrane four times. To conduct, two Ach must bind at the same time (one to each of the two alpha subunits)
What is responsible for the synaptic delay
The main part of the synaptic delay occurs between the time of membrane depolarization and fusion of vesicle and surface membranes. Diffusion across the narrow synaptic cleft and activation of postsynaptic ACh receptors is very fast
- Define synaptic facilitation and how long it lasts
Due to resdual Ca: During repetitive nerve stimulation, Ca concentration in nerve terminal rises b/c the terminal cant get rid of it as fast. The residual Ca left over increases the number of quanta secreted (ie. The second shock will release twice as many quanta as the first). This lasts 1/10 of a second (amount of time it takes to pump Ca out)
- Define synaptic depression and how long it lasts
Due to depletion of vesicles: During repetitive nerve stimulation, the nerve terminal cannot replenish synaptic vesicles from its ‘reserve pool’ fast enough to keep up with demand, so the number of quanta secreted will decrease. Takes about 5 seconds to recover
Does synaptic facilitation or depression usually dominate?
Typically, during repetitive stimulation facilitation is evident first, depression later. But in a healthy person, the minimum number of quanta (~30) are secreted under all conditions, even during intense exercise
If a person with Myasthenic syndrome did an intense activity, would they become weader or stronger?
they become stronger because of synaptic facilitation (synaptic depression is not a problem because so few vesicles undergo exocytosis that vesicle depletion is
not a problem) they become stronger because of synaptic facilitation (synaptic depression is not a problem because so few vesicles undergo exocytosis that vesicle depletion is
not a problem)
What is Myasthenia gravis
Autoimmune disorder in which Abs attack Ach receptors, Thus, the released ACh is less effective, with the result that spontaneous MEPPs and evoked EPPs are reduced in amplitude
If a person with Myasthenia gravis did an intense activity, would they become weaker or stronger?
weaker- Since the Ach receptors are blocked by Abs, it requires more quanta released to trigger an AP. Synaptic depression during intense activity will reduce the vesicle reserve pool and quanta output is also reduced.
Neostigmine
Drug that blocks acetylcholine esterase and thus prolongs currents at neuromuscular junction. Treatment for myasthenia gravis and myasthenic syndrome
Curare
Blocks acetycholine receptors and induces paralysis. Was used as muscle relaxant in anesthesia
Compare synapses at neuromuscular junction to the CNS
NMJ: one skeletal muscle fiber is innervated by only one motor neuron and each AP can trigger enough of a depolarization in the muscle that it contracts. CNS: Each postsynaptic neuron receives inputs from lots of presynaptic cells, presynaptic terminal bouton has a single active zone and releases very few synaptic vesicles, a single AP rarely produces exocytosis of any vesicles and instead multiple inputs are needed to trigger release
List excitatory and inhibitory neurotransmitters/channels
excitatory: glutamate (opens non-selective cation channels), sodium channels, non-selective cation channel. Inhibitory: GABA ( increases chloride permeability), K channels
describe presynapic inibition of transmitter release
An inhibitory nerve terminal will synapse on an excitatory pre-synaptic terminal, creating a sort of synaptic hermaphrodite. The inhibitory nerve terminal releases GABA, which opens chloride channels in its target presynaptic terminal, partially short circuiting the AP in the excitatory terminal, thus reducing number of Ca channels opening and reducing excitatory neurotransmitter release
- Describe the basic mechanism that determines whether a synapse is direct (fast) or indirect (slow).
Fast: (ionotropic receptor) the neurotransmitter directly gates an ion channel and instantly changes membrane permeability. Slow: (Metabotropic receptor) Neurotransmitter binds to a G protein, then second messengers binds to ion channel and opens/closes it, or triggers gene transcription. It is indirect
How are second messenger pathways turned off
phosphodiesterases break down cAMP into AMP or protein phosphatases remove phosphate groups from proteins
Name a typical physiological response mediated slow synapse
Slow: emotions (long and sustained), prolonged sympathetic arousal, modulation of sensory input during various behavioral states, learning
Name a typical physiological response mediated by a fast synapse
Fast: responding quickly to sensory stimulation, spinal reflexes, rapid voluntary motor behavior, visual and auditory perception.
- Describe the conductance (permeability) characteristics of the channel opened in fast excitation. Define the electrical “driving force.” Define the reversal potential for direct excitation.
Reversal potential: the membrane potential at which there is no net (overall) flow of that particular ion from one side of the membrane to the other.
- Describe the kind of channel that is opened during fast inhibition in the CNS.
GABA- increases chloride permeability in the postsynaptic membrane (the chloride equilibrium potential is more negative than threshold for an action potential, and is usually slightly more negative than the resting membrane potential).
- Why is inhibition often more powerful than one might predict from the size of an individual inhibitory post-synaptic potential (IPSP)?
membrane potential is always determined by the relative permeabilities of each participating ion. An IPSP that is only 1 mV in amplitude could reflect a huge permeability
change, if the ion’s equilibrium potential is near the resting potential, such is the case for chloride.
- Define temporal and spatial summation of postsynaptic potentials.
Spatial: Two or more different inputs contribute to the potential, w/o the involvement of facilitation. Temporal: Same input is stimulated in succession before the first potential has completely decayed. Facilitation can play a role in this.
- Describe the three mechanisms for removing transmitters from synaptic clefts in CNS.
diffusion out of cleft, reuptake (by transporters in presynaptic terminal) or destruction (only for cholinergic synapses, there are no enzymes to destroy other neurotransmitters)
What effect does Ach have in autonomic ganglion cells
Both direct and indirect synaptic transmission: It binds to an ionotropic receptor (nicotinic) for fast EPSP, plus binds to a metabotropic receptor (muscarinic) which releases a second messenger that slowly closes K channels, causing a slow EPSP.
Nicotinic vs muscarinic receptors
nicotinic: NMJ, ionotropic, agonist is nicotine, antagonist is curare. Muscarinic: ANS, smooth muscle, metabotropic, agonist is muscarine, antagonist is atropine
What type of receptor do catecholamines bind to
catecholamines (such as epinephrine, norepinephrine, dopamine) bind to slow, G protein coupled receptor
Define synaptic integration
summation of excitatory and inhibitory potentials in neurons
Factors influencing synaptic integration
reversal potential (excitatory or inhibitory), size of each synapse, distance of each synapse from soma/axon hillock, number of excitatory vs inhibitory synapses active and leakiness of neuron
Where are action potentials initiated and why
Trigger zone (aka axon hillock) btw cell body and axon- Threshold at this location is lower (more negative and closer to resting potential) due to a higher density of VG Na channels. So even if an EPSP depolarizes the dendrite more than the trigger zone, the AP will still be initiated at the trigger zone.
In which direction does an AP move
The action potential will propagate not only down the axon, but also back through cell body into the dendrites
- What is a coincidence detector?
Coincidence detectors make synapses smart and are the key to associative learning. They require input from two sources
How does the NMDA receptor work as a coincidence detector?
NMDA receptors require simultaneous binding of glutamate and a postsynaptic action potential to conduct. Glutamate release from the pre-synaptic terminal binds to the NMDA and AMPA receptor on the post synaptic membrane. AMPA is a non selective cation channel, so it opens when it binds glutamate, allowing for an AP to occur. Glutamate opens the NMDA receptor and the AP pops an Mg ion out of the middle of the NMDA receptor, so the receptor is now open. Ca enters the cell
How can activation of NMDA receptors lead to post synaptic strengthening?
When Ca enters the cell via the NMDA receptor, vesicles containing AMPA receptors are released and the AMPA receptors are inserted into the membrane (the same membrane as the NMDA receptors that triggered their release). This increases the size of glutamate induced synaptic potentials (but only at this particular synapse), thereby making it stronger.
How can activation of NMDA receptors lead to pre synaptic strengthening?
entry of calcium ions through NMDA receptor channels into the postsynaptic dendrite promotes the enzymatic synthesis of nitric oxide (NO), which diffuses back across the synapse and potentiates transmitter release from the pre synaptic terminal.
How do NMDA receptors lead to behavioral associative conditioning?
Say a motor neuron receives strong input from one pre-synaptic neuron (capable of producing an AP in the motor neuron) but a weak connection with another pre synaptic neuron (not capable of producing AP on its own). If both the weak and strong neurons fire at the same time, the strong neuron will trigger the AP while the weak neuron will release glutamate at the synapse, thus activating the NMDA receptor. The synapse btw the weak input neuron and the motor neuron will become stronger
- What is long term potentiation, what is Long term depression?
LTP: An increase in the synaptic current produced by a synapse after a pairing event, causing high frequency stimulation of weak synaptic inputs (and subsequently strengthening those synapses) . NMDA receptor plays key role.
what is Long term depression?
LTD: Low frequency stimulation of weak synaptic inputs actually causes the synaptic responses to become smallerdue to endocytosis of AMPA receptors from postsyaptic membrane
What is a silent synapse
In developing brain, newly formed synapses may only have NMDA receptors but lack AMPA receptors on the post synaptic membrane, so initially when the presynaptic neuron fires, the postsynaptic cell has no response. However, after the NMDA receptor has been activated (by both glutamate from pre-synaptic terminal and a post synaptic AP), AMPA is inserted int the post synaptic membrane and the synapse responds normally
Permeability of an ion is determined by _____________, while the direction ions move is determined by ________________
properties of the ion, driving force (Nernst potential)
Diseases that affect spine density
Fragile X (increased spine length with decreased spine density on dendrites), prion disease, alzheimers
