Synaptic physiology

Question 1

Motor neurons in the spinal cord send myelinated axons through ____ roots and peripheral nerves to connect with skeletal muscle fibers

Answer 1

ventral

Question 2

What is synaptic facilitation?

Answer 2

Increased Ca buildup inside the synaptic terminal causes increased vesicle release (more quanta released).

Question 3

What is synaptic depression?

Answer 3

Decreased availability of presynaptic vesicles, leading to a decrease in the quanta of secreted vesicles.

Question 4

Whether a CNS synapse is excitatory or inhibitory is determined entirely by the nature of the receptor. For example, a synapse that opens postsynaptic channels selectively permeable to sodium ions is (excitatory/inhibitory) a synapse that opens postsynaptic channels selectively permeable to potassium ions is (excitatory/inhibitory).

Answer 4

Na = excitatory;

K = inhibitory

Question 5

What happens if the postsynaptic permeability increases to more than one kind of ion? A common example of this is the Non-Selective Cation (NSC) channel, which is permeable both to sodium and to potassium. The reversal potential for this channel is -10 mV, and the threshold for an action potential is about -55mV. Is this excitatory or inhibitory?

Answer 5

Excitatory, because the reversal potential is more positive than the threshold for an action potential.

Question 6

Define electrical synaptic transmission, name a limitation of this form of intercellular communication (compared to chemical transmission), and describe why it would be ineffective at the neuromuscular junction and whether this method of communication is important in the mammalian CNS.

Answer 6

Basically a channel between two neurons (gap junction). The tunnel proteins are called connexins. Action potentials can be transmitted bidirectionally.

Advantages: extremely fast transmission, simple, bidirectional, easy to trigger synchronous activity.

Charcot marie tooth neuropathy (point mutation in the connexin)

Disadvangates: Can only be excitatory, no signal amplification, integration of signals is difficult. Cannot modulate the signal (no learning and memory)

Question 7

Name the presynaptic events involved in transmitter release, from the time of the arrival of an action potential to exocytosis (11 steps)

Name the postsynaptic events involved in synaptic transmission.

Answer 7

AP, terminal depolarizes, Vca channels open, Ca diffuses into terminal, Ca triggers vesicle fusion, excocytosis, diffusion, postsynaptic binding, receptors open and allow positive ions into postsynaptic terminal, depolarize, if threshold potential, AP is generated.

1ms is a good ballpark number for these 11 steps.

Question 8

What differs in the steps at the synapse for the neuromuscular junction as compared to a neuronal junction?

Answer 8

Action potential, Presynaptic terminal depolarizes, Voltage gated calcium channels open, Calcium diffuses into terminal, Calcium triggers fusion of vesicles with presynaptic membrane, !Exocytosis of acetylcholine.
Transmitter diffuses across synaptic cleft, Transmitter binds to acetylcholine receptors on muscle fiber, !Receptors open and allow Na and K ions to enter cell, Depolarization, EPSP, !Action potential on muscle fiber and transverse tubule is ALWAYS elicited, !Ca- release from sarcoplasmatic reticulum, !Muscle contraction, !Acetylcholine is broken down by acetylcholine esterase.

Question 9

Describe the ‘job description’ for a motor nerve terminal?

Answer 9

Reliably transmit the signal to the muscle without any sort of processing. (Big, stupid)

Question 10

Describe how the neuromuscular synapse amplifies the incoming signal in order to depolarize the muscle fiber to threshold for an action potential.

Answer 10

1) Translate the electrical AP into a chemical cascade (releasing 100s of neurotransmitters)
2) Increase the size of the synapse (releasing 1000s of transmitters)

Question 11

Define the safety factor at the neuromuscular junction and discuss whether the why/why not safety factors are present at CNS synapses.

Answer 11

Safety factors are not present at the CNS junction because this would interfere with computation and processing. The safety factor basically ensures that an AP to the NMJ is always translated to a single muscle contraction of the innervated fiber (by release of too much neurotransmitter, and by overexpression of Ach receptors, etc.) Allows for repeated firing, etc.

Question 12

Define facilitation and synaptic depression of transmitter release. Name the underlying mechanism of each.

Answer 12

Synaptic facilitation - more vesicles released for rapid subsequent signals due to Ca accumulation in the presynpatic terminal

Synaptic depression - vesicle supply exhausted, amplitude of signal gets smaller with repeated stimulations

Question 13

Describe the basic mechanism that determines whether a synapse is direct (fast) or indirect (slow). Name a typical physiological response mediated by each.

Answer 13

The basic mechanism is that fast = ionotropic and slow = G protein (or other second messenger) coupled.

The effects of slow synaptic transmission are relatively long-lasting - seconds, minutes or even hours - rather than the millisecond time scale of fast synaptic transmission. Fast reactions of the nervous system (e.g., spinal reflexes, rapid voluntary motor behavior, visual and auditory perception, etc.) undoubtedly involve mainly direct synaptic transmission. Longer-term processes in the nervous system (e.g., prolonged sympathetic arousal, modulation of sensory input during various behavioral states, learning, etc.) probably involve also slow synaptic transmission

Question 14

Describe the conductance (permeability) characteristics of the channel opened in fast excitation.

Define the electrical “driving force.” Define the reversal potential for direct excitation.

Answer 14

Fast excitation refers to a non-selective ion channel activated directly by a neurotransmitter

Driving force: Difference between reversal potential and actual potential.

Reversal potential is calculated with the Nernst equation (for one ion) or the Goldmann-Hodgkin-Katz equation (for multiple ions)

The permeability for particular ions is determined by the properties of the ion channel, the direction in which ions move is determined by the driving force (Nernst equation).

Question 15

Describe the kind of channel that is opened during fast inhibition in the CNS.

Answer 15

Fast synaptic inhibition is driven by GABA, which opens Cl channels to hyperpolarize the membrane and quench an action potential. Remember that the size of inhibition depends on the relative permeability of the membrane to the ion, as well as the resting potential (so a small inhibitory voltage change may have a seemingly disproportionate inhibitory effect).

Question 16

Describe why inhibition is often more powerful than one might predict from the size of an individual inhibitory post-synaptic potential (IPSP)?

Answer 16

One reason is that they are closer to the cell body (EPSP are generally further out on the dendrite).

It also depends on the relative permeability of the ions in question, relative to the resting membrane potential.

Question 17

Define temporal and spatial summation of postsynaptic potentials.

Answer 17

Temporal: Repeated EPSP on the same presynaptic neuron

Spatial: Several EPSP from different presynaptic neurons

Question 18

Describe the three mechanisms for removing transmitters from synaptic clefts.

Answer 18

Diffusion, reuptake, and destruction.

Calcium sodium antiporters can remove Ca from the cleft
Vesicular membrane reclamation by clathrin and dynamin
Neurotransmitter reuptake by neurons or glia, or enzymatic breakdown

Question 19

Define a coincidence detector and describe how the NMDA receptor works as a coincidence detector.

Answer 19

To open, the NMDA receptor requires depolarization from an outside source + glutamate binding. The external “gate” is opened by glutamate. The channel, however, will be blocked by Mg+, whose positive charge is attracted to the negatively charged interior of the cell.

If a cell is depolarized, the Mg+ will dissociate, and glutamate binding to the NMDA receptor at this time will result in Ca influx into the cell.

Question 20

Describe how activation of the NMDA receptor can lead to synaptic strengthening and how such a mechanism might lead to behavioral associative conditioning.

Differentiate between postsynaptic strengthening and presynaptic strengthening.

Answer 20

Postsynaptic strengthening: Entry of calcium into the POSTsynaptic terminal causes exocytosis of vesicles (just like in the presynaptic terminal). However, these vesicles contain AMPA receptors in place of neurotransmitters. INcreased numbers of AMPA receptors in the postsynaptic membrane increases the sensitivity to glutamate at this specific synapse, strengthening it. It will remain strong for as long as the number of AMPA receptors remains high, which could be a long time.

Presynaptic strengthening: Activation of NDMA in the POSTsynaptic membrane causes synthesis of NO which diffuses retrograde and potentiates transmitter release in the presynaptic terminal (possibly by activating release of calcium from internal stores in the presynaptic terminal.)

Question 21

Define LTP (Long Term Potentiation) and LTD (Long Term Depression) and how each is involved in learning and memory.

Answer 21

LTP: an increase in the synaptic current produced by a synapse after a pairing event. (Pavlov’s dog) LTP is the result of AMPA receptor addition into the postsynaptic terminals activated by the CS (conditioned stimulus).

LTD: The opposite effect. A decrease in the synaptic current produced by a synapse after a pairing event. (Somehow linked to low frequency stimulation, instead of the high frequency stimulation involved in Pavlov’s classic experiment. [notes])

**[lecture] Why one of these vs the other occurs in response to a certain level of stimulus is not yet known. It is simply tested experimentally.

Question 22

Myasthenic syndrome is caused by

Answer 22

An autoimmune reaction against the Cav channels in the active zone of the presynaptic neuron of a neuromuscular junction. Transmission will be slowed.

Do not confuse this with myasthenia gravis, they are not the same condition.

Question 23

What are the proteins involved in the SNARE complex? Differentiate between those associated with the vesicle versus the host membrane.

Answer 23

VAMP: Vesicle Associated Molecular Protein (aka Synaptobrevin, v-snare)

Target Associated (t-snare): SNAP25 and Syntaxin. I believe SNAP25 is the infamous “coiled-coil”

A molecule called “synaptotagmin” is responsible for Ca sensing, which is required for the fusion to proceed to completion.

Question 24

What is the primary difference between the following types of vesicle fusion: “Kiss and run” vs “complete fusion”?

What proteins are involved in each process?

Answer 24

In “kiss and run,” the vesicle does not fuse completely with the membrane. NSF untangles the SNARE complex.

Full fusion uses the same proteins, but also requires clathrin and dynamin (to pinch off the vesicle).

Question 25

Botox (botulism toxin) method of action and location

Answer 25

Binds in the PREsynaptic terminal, and selectively prevents release of EXCITATORY neurotransmitters (Ach, specifically) resulting in flaccid paralysis.

(The toxin acts as a protease that diffuses through the synaptic junction, cleaving various SNARE proteins. One molecule of toxin can cleave many proteins [ie it is not consumed] which is what makes it so potent. Specific to the neuromuscular junction.)

Question 26

Tetanus toxin

Answer 26

Binds in the PREsynaptic nerve terminal, preferentially prevents release of INHIBITORY neurotransmitters (Glycine, GABA), resulting in muscle spasm. Specifically, it cleaves synaptobrevin II.

**Remember with regard to botulism/tetanus - mode of action is very similar, but the site is different so you get a different result. Affects neurons in the CNS. Can treat with benzodiazapenes.

Question 27

What neurotransmitter is active in the NMJ?

In the CNS (3). Of these, which are excitatory/inhibitory?

Answer 27

Neuromuscular junction: acetylcholine

CNS: glutamate(+), glycine(-), GABA(-)

Question 28

What is a MEPP?

Would you see MEPPS in a synapse treated with low Ca? With curare?

Answer 28

MEPP: Miniature End Plate Potential (aka “mini”): the spontaneous release of one synaptic vesicle across the synapse. The observation of these symmetrical events led to the quantum theory of the synapse–that transmitters are released in discrete packets, or “quanta” (Katz 1950)

Low Ca–> Yes MEPPS
Curare–> No MEPPS (they would still be released, but you wouldn’t be able to see them in the POSTsynaptic voltages)

Different amplitudes of postsynaptic potential occur in discrete multiples of these quanta, but not fractions of (although the packet sizes follow a bell curve distribution).

Question 29

Nicotinic receptors: Location? Ionotropic or Metabotropic?

Muscarinic receptors: Location (general)? Io/Meta?

Answer 29

Nicotinic: neuromuscular junction, ionotropic,

Muscarinic: autonomic NS, smooth muscle, metabotropic

Question 30

Myasthenia gravis vs myasthenic syndrome

Answer 30

Myasthenia gravis: Antibodies to postsynaptic ach receptors. Patients are weak and become weaker with exercise (due to depression). Often present with fine motor weakness (ptosis)

Myasthenic syndrome: Ab to the presynaptic Ca channels. Patients are weak and become stronger with exercise (due to facilitation). Often present with trunk weakness.

Question 31

Tx compound mentioned in lecture for M gravis and Myasthenic syndrome?

Answer 31

Neostigmine. Blocks Ach esterase to prolong current at the NMJ.

Question 32

What is curare?

Answer 32

Ach receptor blocker to induce paralysis. Modern analogs of this are used with general anesthesia as a muscle relaxant, allowing much lower doses of sedative.

Question 33

Fragile X syndrome.

Answer 33

Increased spine length and decreased spine density

Question 34

What might a GABA reuptake inhibitor be used to treat?

Answer 34

May be used to treat seizures, epilepsy, convulsions,

anxiety disorders, for anesthesia.

Question 35

What are 5 factors that influence neural integration (signal strength with regard to the EPSP/IPSP)

Answer 35

Reversal potential (excitatory or inhibitory)
Size of each synapse
Distance of each synapse from soma/axon hillock
Number of excitatory vs. inhibitory synapses active
‘Leakiness’ of neuron

Question 36

Compare/contrast the NMJ vs the central synapse in terms of: Speed, effect, strength, safety factor, transmitter, termination, information processing

Answer 36

Central: Fast or slow, can be excitatory or inhibotory, mostly weak, no safety factor, all transmitter types, termination = uptake, information processing = yes (smart)

NMJ: Fast, excitatory, strong, yes safety factor, Ach, Termination by diffusion/ach esterase, no processing (stupid)

Question 37

Differentiate synaptic facilitation from summation.

Answer 37

Facilitation increases signal size.

Summation increases signal frequency.

These can occur independently of one another, or concurrently.

Question 38

What is an EPP?

Answer 38

An EPP (End Plate Potential) is a depolarization of the POSTsynaptic terminal that fails to reach the depolarization threshold (ie the Nav channels do not activate). In our lab, we discussed that roughly 30mV are required to reach depolarization threshold, and each vesicle transmits about 1mV, so up to 29 vesicles could theoretically be released without triggering an AP and subsequent contraction.

Question 39

What effect does bathing the NMJ in curare have?

Answer 39

Nicotinic receptors are blocked, so the muscle cannot contract even with the release of Ach from the presynapse.

Question 40

What effect does bathing the NMJ in low Ca have?

Answer 40

Affects the presynaptic terminal’s ability to release vesicles. High intracellular Ca levels are required. So, the muscle won’t contract.

Question 41

What effect does neostigmine have on synaptic transmission? Describe the drug’s mechanism of action.

Answer 41

Neostigmine is an AchE blocker. At pharmacological doses it will increase the half-life of Ach in the synapse, allowing 1) more to cross to the postsynaptic membrane and 2) prolonged t1/2 so a given molecule can associate/disassociate multiple times.

At toxic levels, neostigmine binds the nicotinic receptor, causing paralysis (to bind AchE it must, after all, mimic the structure of Ach to some degree).

Question 42

At what frequency (Hz) can APs be conducted? At what frequency can contractions proceed? What happens above the contraction threshold?

Answer 42

AP = 600Hz
Contractions = 20-25 Hz

Above 25Hz = tetany

Question 43

On the ascending slope of an action potential (as in the frog muscle fiber experiment), what accounts for the initially lower slope, which then becomes steep?

Answer 43

Initial slope = activation of nicotinic Ach receptors (ionotropic)

Steep slope = depolarization threshold reached, activation of voltage gated Na channels

Question 44

Why is boltulism more common in CO?

Answer 44

High altitude–> water doesn’t boil as hot, so don’t kill all the organisms/spores.