Lecture 18.docx

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Cell and Systems Biology
Francis Bambico

 The placement of the electrode  In this experiment demonstrating associative LTP, you need two nerves/axons – simultaneous activation of axons  One of the electrode in this area, it’s possible because if you place it anywhere, it’ll still stimulate the neuron  Other electrode (clear way of placing the electrode), the AP travel to the dendrites  But you can place the electrodes anywhere as long as it stimulate 2 different axons/nerves  If you place it close to both nerves/axons, it’s going to create something ______?  Bottom line of associative LTP: you have to stimulate 2 axons and if you go back to the postulate, he says that associative LTP occurs when a post synaptic neuron is stimulated simultaneous with the stimulation of a presynaptic axon  So simultaneous activation of the post synaptic neuron and pre synaptic will result in the strengthening of that synapse so cells that fire together gets wired together; increase synaptic efficacy  This will be modified later on by a neuronal postulate modification that says it’s not sufficient to just stimulate simultaneously, you have to also make sure the pre synaptic neuron gets stimulated first before you stimulate the post synaptic neuron -______ plasticity  In this exp, pre synaptic stimulation using a tectanus form of stimulation (high freq stimulation), that will lead into the strengthening of the synaptic connection  How would you test that it has increased? By the amplitude of the strength of the EPSP resulting from a test stimulus  Apply a test stimulus (1 AP/depolarization current) and then record EPSP  Increase in amp -> strengthened  For associative LTP, let’s go through the procedures they did o They were testing the changes in synaptic connectivity; stimulus 2 is applied to axon 2 o Tried to figure how the synapse between axon 2 and ca1 pyramidal neuron gets strengthened 1. test of the baseline activity of the synapse by applying a test stimulus in the presynaptic axon and then record the resultant EPSP in the post synaptic neuron 2. say tectanic stimulation was applied (50 Hz for 5 sec) then test the evoked EPSP by test stimulus and then record and you get no change in amp; why? The freq/stimulation is not enough 3. apply another stimulation with a higher freq (100 Hz for 5sec) on axon 1(another axon) and then record and examine the changes in EPSP resulting from test stimulus on axon 2 (what you’re testing) -> see no change in amp because high freq at a different axon; it’s possible to trigger an increase in synaptic efficacy not in this axon but the synapse; if you apply the test stimulus to the synapse, you might see an increase in PSP; LTP could occur there but not in the axon; this low freq is not sufficient to cause an increase in amp in EPSP 4. only under the condition of simultaneous stimulation of axon 1 and axon 2 and then wait after 4-10 mins and record from post synaptic neuron, then you’ll see an increase in amplitude  bottom line of associative LTP: a weak stimulation that normally does not produce an increase EPSP would produce an increase in amp when the stimulation is paired with a stronger stimulation  you need another axon stimulated to help the weak axon to increase the connectivity between the synapse  mechanism of associative LTP  something to do with NMDA receptors and amp type glutamate receptors  both ionotropic receptors permeable to cations (Ca, Na, K)  the difference is that NMDA, under the resting condition, is plugged by another cation, Mg, which prevents the influx of other cations slide 5  suppose this is your post synaptic neuron and this is axon2 and that is axon 1  this is the weak one that if you stimulate, it’s not going to give a change in EPSP  stimulating these axons would result in the release of glutamate that would bind to 2 of these receptors, AMPA and NMDA  bind AMPA -> increase in influx of Na and some Ca -> would depolarize the post synaptic neuron  But entry of Ca results in a small release of glutamate; it’s not enough to sufficiently depolarize the post synaptic dendrite to be able to increase the membrane potential enough to expel the Mg from NMDA receptors  If you pair this weak stimulation with a strong stimulation, axon 1; if you stimulate them together, this axon will depolarize the post synaptic neuron of course but it work in coop with axon 2 so you will depolarize the post synaptic more; increase Na, Ca from both axons would pass depolarization to the post synaptic neuron to reach a threshold that would be sufficient to expel Mg from NMDA receptors and that would result in increase of influx of Ca through NMDA receptors  Ca would activate many biochemical pathways resulting in the strengthening of the synapse  If there’s a sufficient amount of Ca inside the post synaptic neuron, Ca conc will bind with CaM and CaM would result in activation of Calcium-calmodulin kinase 2  When this gets activated, it’s going to autophosphorylate itself for a long time -> series of biochemical pathways that would result in insertion of additional ampa receptors on the post synaptic membrane -> the next time you stimulate the weak axon, it’s stronger because there are more ampa receptors -> increase in Na and Ca influx in the post synaptic neuron -> increase in amplitude  NMDA is important; associative principle; detects the condition when the pre or post neuron is active while the post synaptic neuron is sufficiently active/depolarized  This is an illustration of what’s happening; summary of the 2 processes; illustration of the biochemical pathways in associative LTP  Results in synthesis of retrograde signaling; they’re produced in addition to the insertion of AMPA receptors, retrograde signals are produced
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