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Physiology and Pharmacology 2 > Synaptic Integration: Lectures 15-20 > Flashcards

Synaptic Integration: Lectures 15-20 Flashcards

1
Q

Where are neurotransmitters stored?

A

Most (glutamate, GABA-glutamate, Noradrenaline, Acetylcholine) are stored in vesicles 40-50nm. Neuropeptides and somatostatins are contained in larger denser vesicles (>100nm)

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2
Q

Why are neurotransmitters stored in vesicles?

A

Management of concentration Protection from degradation Regulation

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3
Q

How are vesicles produced and recycled?

A
  1. Components of synaptic vesicle delivered to plasma membrane 2a. Endocytosis of synaptic vesicle to form new vesicles directly 2b. Endocytosis of components and delivery to endosome 3b. Budding of synaptic vesicle from endosome 4. Loading of neurotransmitter into synaptic vesicle 5. Secretion of neurotransmitter by exocytosis in response to an action potential. Insert diagram
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4
Q

How is neurotransmitter released?

A

Stimulation (depolarisation- either natural or induced) leads to vesicular fusion with plasma membrane Dependent on calcium.

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5
Q

Why is neurotransmitter release dependent on calcium?

A

The two are cooperative: Ca2+ influx –> 3 or 4 fold increase in release.

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6
Q

What is the influx of calcium triggered by?

A

Voltage gated calcium channels of different types: - L: long lasting - P/Q: transient - N: neither (Neural) - R: resistant (residual)

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7
Q

What is the ionic requirements for a release of neurotransmitter?

A

Elevation in intracellular calcium levels - Not related to Na+ or K+ -Single channel opening unlikely to cause release

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8
Q

Where are the calcium channels located?

A

Close to the binding site in order to create the largest rise in intracellular calcium levels possible.

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9
Q

Why are P/Q channels so important?

A

Responsible for all ACh release and the majority of Ca2+ mediated release. - no other channel can compensate for ACh release - R and N channels can compensate for Ca2+ mediated release.

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10
Q

How is the amount of vesicular release quantified?

A

Electrical signal generated from the post-synaptic membrane is proportional to amount of neurotransmitter binding. Increase neurotransmitter –> increase PSP

Mini: release of individual vesicle at the neuromuscular junction, roughly equivalent to 10,000 molecules of Ach. This produces a mini PSP.

  • Further electrical stimulation –> depolarisation in multiple of mini
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11
Q

Define Quanta?

A

Quanta: release of individual synaptic vesicles at the neuromuscular junction

Quantal release in the thalamus evokkes an excitatory post synaptic current (doesnt always have to be excitatory)

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12
Q

What evidence is there at vesicular release is quantal?

A

Depolarisation is a multiple of minis

K+ channel blockers –> similar response

Mean number of quanta = mean amplitude of EPSP, depending on probability (size and shape of depol, state of calcium channels, baseline calcium level, number of docked / primed vesicles, phosphorylation of presynaptic proteins)

Binomial probability

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13
Q

Explain binomial probability

A

Number of vesicles (n) is equal to the number of trails

Each trail has (p) probability of success

  • Trails are independent so do not affect one another

N * P = mean of distrubution

N*P*(1-p)= variance –> SQR –> SD

Q = quantal context (mean mini ampltidue

Therefore: N*P*Q or N*P*(1-p)*Q

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14
Q

What links does vesicular release have to other things?

A

Inflammation- increases the release probability of vesicles –> pain

Nerve ligation (phosphorylated GluR1 receptor) –> increased probability of release

Botox blocks release of vesicles to prevent contraction of facial muscles

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15
Q

Define a channel:

A

When open provides a continous pore through the bilayer, allowing the flow of many ions

Cycles between open and closed conformations

Gated by: ligands, voltage, membrane stretch (leakage)

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16
Q

Define a transporter:

A

Solute binding site

Avaliable on one side of the bilayer or the other

Carries a few solute molecules per cycle.

  • Slower than channels
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17
Q

What types of transporters are there?

A

Uniport = 1 ion’s path through

Symport = 2 ions transported together

antiport= 1 ion in 1 ion out

Can be active (ATP requiring, against gradient) or passive (down the gradient)

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18
Q

What are some examples of passive transporters?

A

GLUT- : transports glucose into cells

Cl-/ HCO-3 anion exchanger : regulates pH

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19
Q

What are examples some examples of active transporters?

A

Ca2+ ATPase, Na+:K+ ATPase - both in plasma membrane

H+K+ ATPase: in parietal cells (acidic environments)

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20
Q

How do transporters cooperate?

A

Active transporters can aid passive (Na+:K+ ATPase aids glutamate transport)

3Na+ and 1 H+ in and 1K+ out for 1 glutamate in

Also true for GABA transporters (1+ net uptake)

2Na+ and 1Cl- in for every GABA in.

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21
Q

What is electrochemical potential

A

If there is a potential difference in charge / concentration ions can diffuse through open membranes

Equilibrium potentials can also be calculated using the Nernst Equation = Eion= RT/zF x ln([ion]out/[ion]in)

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22
Q

Give some examples of reversal potentials?

A
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23
Q

How is glutamate transported?

A
  1. Glutamate converted to glutamine in glial cells
  2. Transported to pre-synaptic cells
  3. Glutamine converted back to glutamate
  4. Loaded into vesciles and then transported across the synapse
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24
Q

Where are glutamte transporters located?

A

Glial cells

Pre and post-synaptic cells

Close to terminal as increased stimulation –> increased transportation

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25
Where are GABA transporters localised?
Pre- and post synaptically On glial cell (GABA --\> GABA transaminase --\> Glutamate)
26
What is the link between glial and glutamte transporters?
1 to 1 relationship at the climbing fibre - Purkinje Cell synapse Prevents glutamte spillover
27
What are the effects of Glutamte spillover
Slow rising CF-EPSC Prolonged IPSCs (in mice) Abnormal motor behaviour
28
What is the role of synapses, transporters and neurotransmitters in ischaemia?
1. Decreased cerebral blood flow --\> decreased ATP 2. Leads to increased intracellular ion (Na, Ca, Cl, H20) and extracellular K+ concentrations 3. Leads to neurotransmitter release 4. Increase Ca inside the cell 5. Cell death and damage
29
What link does calcium have to cell death and damage
Influx driven by glutamte through NMDA and AMPA receptors. Released from intracellular stores and enters through VGCC. NMDA receptor antagonists prevent damage Complete interuption of blood flow to brain for 5 minutes --\> severe damage to core zone Leads to disruption of ionic graident --\> glutamate in a non-calcium dependent manner.
30
How complex is the human nervous system?
10^14 synapse 11^11 neurons
31
Why is synaptic integration important?
Neurons recieve multiple input and provide multiple outputs. Integration allows for information processing and determines nervous system function
32
What affects synaptic integration?
**Neuronal morophology and distribution** - complexity, distance from soma, relative positioning **Synaptic properties-** amplitude of current flow at synapse, AP firing **Membrane potentials** - time constant --\> temporal summation, contact sites simultaneously activated - length constant --\> spatial summation --\> PSPs from different neurons summate.
33
What affect does synaptic integration have on output?
Total effect on soma membrane potential is the summation of all synaptic potentials
34
What is the purpose of Purkinje cells?
Integration of neurons in the cerebellum Recieves input from climbing fibre and parrallel fibre
35
Describe a climbing fibre:
1 per Purkinje Cell but with many synaptic connections Large synaptic current can trigger complex spike
36
Describe a parallel fibre:
Each purkinje fibre recieves thousands of parallel fibre inputs, but only one contact site
37
Describe syanpses across a purkinje cell, why are there so many?
Size of synaptic input is unimportant because it can summate causing the threshold to be reached?
38
Why does length constant affect spatial synaptic integration?
Amplitude reduces with distance based upon the length constant. This is determined by membrane resistance and axial resistant as I= SQRT( Rm/ Ra) Decrease Rm --\> decreased leakage Lower axial resistance --\> less resistance along dendrites
39
Does it matter where the inputs come from
Inputs arrive from same distance to soma --\> depolarisation = input 1 + input 2 Inputs arrive from different distance --\> Depolarisation doesnt equal input 1 + input 2 - Earlier membrane potential causes ion channel opening, changes in membrane resistance and changes in the length constant. - Makes it harder for the second input to spread.
40
How does temporal summation work?
A train of action potentials arrive. If the PSP and time constant short then there is no temporal summation due to the decay of the first input If PSP and time constant longer this can lead to summation where one PSP superimposes on earlier. Decay is linked to time constant which depends on membrane reistance and capacitance t= Rm x Rc - Less leakage --\> increased increase till decrease - More charge is stored and discharged
41
What is the difference between temporal integration and coincidence detection?
Short time coincidence - coincidence detection, as EPSPs must arrive 'simultaneously' to summate Longer time constant- greater period allowed for summation, so frequency of AP's important --\> temporal integration
42
What is a temporal integrator?
Requires a long-time constant? Most / all EPSPs contribute to final APs Output is independent of input in terms of timing Output / activity proportional to input activity
43
Describe coincidence detection:
Short time constant so the timing of inputs are crucial - only coincidenct inputs produce an action potential
44
What do excitatory and inhibitory inputs correspond to?
**Excitatory** Inflow of positive charge - Na+ flows in **Inhibitroy** Positive outflow or negative inflow - K+ out or Cl- in
45
What happens when you combine an excitatory and inhibitory input?
PSP output will have a membrane potential somewhere between the two inputs
46
Describe linear summation:
Excitatory and inhibitory synapses arrive from the same distance to the soma on different dendrities Leads to combined effect
47
Describe what happens when there is an inhibitory synapse between the excitatory synapse and the soma on the same dendrite:
NON-linear summation - Counteracts the current flow initiated at excitatory synapse (outflow of the positive charge), due to a lower of membrane resistance - change in the length constant - This affects the spread of the EPSP - The two PSPs combine in an unpredictable manner
48
Describe uncoupling of dendrites by inhibitory synapses?
Blocks the propagation of synaptic potentials to the soma. Excitatory input is only recieved from dendrities with no inhibition
49
What is silent postsynaptic inhibition?
Synaptic Reversal Potential = Resting membrane potential - Inhibitory PSP's will have no affect on membrane activity despite being completely active, until it combined with an excitatory input - Causes an **inhibitory shunt** on excitatory input
50
What mechanism does silent postsynaptic inhibition work by?
Ohms Law: V= R x I Where V= change in Vm, R= membrane resistance and I= synaptic current Inhibitory inputs --\> decrease in membrane resistance --\> decreased change in Vm
51
What is a good example of silent post-synaptic inhibition?
GABA- main inhibitory neurotransmitter in mammalian CNS. Works via Chlorine channels- chlorine's reversal potential is close to resting membrane potenital
52
How do you study temporal and spatial integration? Problem: Normal recordings even if only one neuron activatied --\> multiple synapses
**Computational modules:** - As good as underlying assumptions, model and diagram - need to check real data **Photolysis of caged neurotransmitters:** UV light releases glutamate which was previously kept inactive. Neuron filled with fluroscent dye to visual process. UV light applied to small specific areas - input --\> output (patterns --\> distinct responses)
53
What is homonsynaptic short-term synaptic plasticity
Variation in amplitude of synaptic potenitlas due to prior activity. Occurs mainly during high frequency stimulation Can either be facilitative- synapse become more effective Or depressive: synapse become less effective - Requires a long gap between action potentials to reset
54
What are some examples of homo-synaptic short-term synaptic plasticity?
Climbing fibres undergo synaptic depression Parallel fibres undergo synaptic facilitation Schaffer collateral undergoes synaptic facilitation then depression
55
How is homosynaptic short-term synaptic plasticity classified?
Paired-pulse ratio: Second pulse larger than the first- ratio \>1 = facilitation Ratio \<1 = depression
56
What is the mechanism for synaptic facilitation?
1st Action Potential causes Ca2+ influx --\> release of transmitter and priming of other vesicles (increase in the number of primed vesicles) 2nd action potential --\> greater release of neurotransmitter A train of AP's leads to spike broadening - longer depolarisation, greater Ca2+ influx, increased neurotransmitter release, increased synaptic response
57
What is the mechanism for synaptic depression?
1st Action Potential --\> release of neurotransmitter from docked vesicles --\> less vesicles dock 2nd Action Potential --\> decreased release of neurotransmitter Leads to progressively weaker post-synaptic potentials
58
Is there any pattern between the probability of synapse firing and faciltation or depression.
High probability synapse is associated with synaptic depression Low probability synapses are associated with synaptic facilitation as more neurotransmitter can be primed.
59
Define homosynaptic:
1 pre-synaptic neuron to 1 post-synaptic
60
Define Heterosynaptic:
More than one pre-synaptic input
61
How are heterosynapses post-synaptically modulated? Give an example
Modulatory input alters postsynaptic membrane sesnsitivity to neurotransmitter E.g. GABAa receptor modulation by phosphorlyation - Activation of PKA --\> phosphorylation of GABAA ==? enhancing or suprresion depending on site - Can lead to a change in receptor number --\> change in sensitivity. - Insulin promotes receptor addition, BNDF promotes removal
62
How are heterosynapses pre-synaptic modulated
Modulatory input affects pre-synaptic transmitter release- either inhibitory or facilitation Inhibitory input causes a removal of excitatory input --\> reduced Ca2+ influx --\> reduced neurotransmitter release --\> reduced PSP
63
What is an example of heterosynaptic facilitation?
Gill siphon withdrawal reflex in *Aplysia californica* Sensitisation Tactile stimulation --\> weak response Tail shock --\> tactile stimulation --\> enhanced withdrawal response
64
What is the mechanism for heterosynaptic facilitation?
Serotonin (5-HT) activates receptor --\> activation of adenylyl cyclase --\> increase in cAMP --\> activates PKA --\> phosphorylation of VGKC --\> reduced K+ outflow --\> AP broadens --\> more Ca2+ influx --\> increase neurotransmitter release
65
What are the different mechanisms for synaptic modulation
**Pre-synaptic** * altered vesicle release * altered Ca2+ entry * altered vesicle recycling **Post-synaptic** * Altered receptor function * Altered receptor number
66
What is long term potentiation? Why is it dependent on plasticity?
A short burst of high frequency stimulation (tetanus) causes an elevated EPSP afterwards. - Causes a lasting effect in the slope of the EPSP, this can last for a long time
67
Why is long-term potentiation important?
Reveals that the hippocampus is important for learning and memory (first discovered there) - If removed then no new memories can be saved/ generated. (patient HM)
68
What forms of long-term synaptic plasticity are there?
**Long term-potentiation** **Long term-depression** Can be NMDA receptor dependent or independent - can lead to long or short term changes in synaptic strength

Physiology and Pharmacology 2 (10 decks)

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