Lecture 12 - Long Term Potentiation

Question 1

Who was Ivan Pavlov?

Answer 1

-Russian scientist/physiologist interested in digestive enzymes
-he wanted to see which foods would create salvary enzymes in dogs

Question 2

What experiment did Pavlov do?

Answer 2

-operation on dogs –> inserted a tube in their cheek, connect it to a beaker and measure the salvation of the dogs in response to food
-realized that after a few experiments, the beaker started filling up before they were presented with food (anticipation)

Question 3

What are the possible neuronal pathways explaining why the dogs drool in anticipation?

Answer 3

-food itself will evoke the salivary response (this pathway [food –> drool] is built into dogs)
-being brought to the test lab could also cause anticipation
-recognizing that the lab assistant often brings food
-Pavlov taught the dog to respond to the bell (would ring it right before or at the same time as food came out)

Question 4

Which pathways were the best indicators of food?

Answer 4

-dogs realized that they were not always fed in the test lab and by lab assistant (not reliable indicators; synapses weakened; LTD)
-the bell is the strongest association (because every time the bell was rang, the dog got food) –> synapse to drool neuron becomes stronger (LTP)

Question 5

How would extinction work in this experiment?

Answer 5

-if Pavolv kept ringing the bell and didn’t feed the dog, the dog would eventually stop drooling to the bell
-extinction: undoing an association that they had made (new learning)

Question 6

What is LTP and LTD?

Answer 6

-LTP: long-term potentiation (stimulating synapse enough over time increases the strength of the synapse) [mainly studied in hippocampus and cortex]
-LTD: long-term depression

Question 7

How do we measure how much excitation we get in the post-synaptic neuron when the Glu neuron is stimulated?

Answer 7

-excitatory synapse in hippocampus or cortex
-put a stimulating electrode in the Glu pre-synaptic neuron and put a recording electrode in the post-synaptic neuron;
-the recording electrode is looking at excitatory post-synaptic potentials

Question 8

What happens when there is medium frequency stimulation?

Answer 8

-stimulate excitatory pre-synaptic neuron, and the post-synaptic neuron would show normal depolarizations of the membrane or normal EPSPs
-normal response no matter how much you stimulate it

Question 9

What happens when there is high frequency stimulation (tetanus)?

Answer 9

-eventually, there is a much greater depolarization of the post-synaptic membrane
-putting it away for a day or week and doing medium frequency doesn’t change anything, still get this exaggerated potentiated response
-this is potentiation

Question 10

What is the concept of LTP?

Answer 10

-if you repeatedly give a high-frequency stimulus to pre-synaptic neuron –> get potentiated response even at lower frequencies in the post-synaptic neuron

Question 11

What are the 2 things that are argued about LTP?

Answer 11

-effectiveness of the synapse to cause a post-synaptic neuron to fire can be changed with higher stimulus
-we consider this whole thing a form of neuroplasticity because different synapses can take over who fires where

Question 12

What is neuroplasticity?

Answer 12

-idea that LTP occurs and that we can strengthen or weaken synapses in the brain
-and neurons themselves can change their shape, grow new connections
-idea that our brain is constantly reshaping itself
-a lot of this is function of learning

Question 13

What happens when the food neuron binds to the drool neuron, according to the Pavlov pathway?

Answer 13

-where the food neuron binds, there are AMPA receptors
-when the food neuron fires, the drool one always fires –> Glu input into post-synaptic drool neuron is highly excitatory, enough so that it’ll reach threshold and fire
-when food is presented, the post-synaptic membrane of drool neuron becomes depolarized (goes from -70 to -40 or higher)

Question 14

Does the drool neuron fire as a result of the bell neuron?

Answer 14

-bell neuron has some Glu but not enough to make the whole drool neuron fire (less important input)
-the synapse where the bell neuron binds has NMDA and AMPA receptors

Question 15

What is the whole process after the bell rings?

Answer 15

-bell rings,
-neuron fires,
-releases Glu into synapse,
-Glu binds to AMPA and NMDA receptors causing all of the receptors to open,
-but no ions flow through NMDA receptors (because Mg2+ is stuck in the channel),
-Na+ flows in and K+ flows out through AMPA receptors,
-nothing really happens with NMDA receptors (silent receptors), [to make sure we don’t get overstimulated by irrelevant information],
-bell is not that relevant to drooling

Question 16

What happens to the membrane when the bell is rung before or at the same time as food is given?

Answer 16

-if at the same time or just before the food neuron is firing, our bell neuron fires, it releases Glu onto its receptors at the same time as the food input is depolarizing our membrane;
-because our membrane is now depolarized, it causes our Mg2+ not to be so attractive because there’s no negative charge pulling the Mg2+ down into the channel and clogging it;

Question 17

What happens to Mg2+ when the membrane becomes depolarized?

Answer 17

-so as the membrane becomes depolarized, Mg2+ pops out of our NMDA receptor;
-now, instead of just ions flowing through our AMPA receptors, we also have ions flowing through our NMDA receptors
-thus, the bell neuron is having a larger effect on the depolarization of the membrane

Question 18

What other ions flow through NMDA receptors?

Answer 18

-NMDA receptors also allow the flow of Ca+ (which is a second messenger)
-Ca2+ binds to CaMKII
-CaMKII can travel to nucleus of the cell and act as a transcription factor (binds to various genes in DNA and promote increased or decreased expression of certain proteins [changing what kind of protein the neuron is making])

Question 19

What are the 5 steps of LTP?

Answer 19

1. NMDA receptors lose the Mg2+ channel blockers [short-term event behind LTP; during learning]
2. Ca2+ flows into post-synaptic neuron [short-term event behind LTP; during learning]
3. increase in post-synaptic AMPA receptors
4. increase in post-synaptic membrane/synapse
5. increase Glu release

Question 20

What is the consequence/result of LTP (step 2)?

Answer 20

-post-synaptic neuron (now that it has CaMKII) starts making and delivering more AMPA receptors [on post-synaptic membrane]

Question 21

What happens when there is an increase in post-synaptic AMPA receptors (step 3)?

Answer 21

-the morphology of the synapse itself changes –> the post-synaptic neuron decides that the bell is an important input so it builds a bigger synapse
-post-synaptic membrane invaginates the pre-synaptic membrane, giving more post-synaptic membrane around the input, so that the overall surface of area of synapse is bigger (thus accommodating all extra AMPA receptors)

Question 22

What happens after the post-synaptic membrane expands (step 4)?

Answer 22

-bell neuron itself starts releasing more Glu
-now, even in the absence of food, the drool neuron can fire to the bell alone even without the food

Question 23

How does the bell neuron know to start increase Glu production/firing?

Answer 23

-reverse transmission: post-synaptic neuron releases NO2 (nitric oxide) to pre-synaptic neuron to cause it to release more Glu
-NO2 is fat-soluble, so it can flow from post-synaptic neuron to the pre-synaptic neuron and act as a reverse messenger

Question 24

What drug behaves like NO2?

Answer 24

-the only other reverse transmission that we are aware of is the Cannabinoid receptors
-post-synaptic neurons release cannabinoids, then they float across the membrane and act on cannabinoid receptors on the pre-synaptic neurons (because they are fat-soluble)