We are going to first talk about a little bit about the short term modulation, okay? The short term modulation and then we are going to talk about the long term modulation, LTP and LTD that I just mentioned. Okay, it could be people artificially separated by 30 minutes, okay. So this is the so called paired pulse facilitation and if you look at time course here, it's relatively short, okay. And this is the one form of a short term pulse facilitation. How do you do it? Well, in a sense set of synapse, if you are deliver two stimulation. And if these two stimulation are relative, far away from each other, in term for example, separated by 300 milliseconds or longer. What you observe is that there is no relative change of the amplitude for the synaptic response. Okay, but if the stimulation are relatively short in time, one can observe that following the initial stimulation, the second stimulation actually has a higher response probability, okay? And this is called facilitation, okay. For example, in this case you can also see even separate by 50 milliseconds in this synapse, that the response will be increase, okay? Those are called paired pulse facilitation because it use a pair of stimuli. And people believe that at least in some synapse have been demonstrated that the reason why you have this facilitation is because of this residual calcium, okay? Because in the initial stimulation, we know that a transmitter reduce in calcium is a non-linear curve. In the initial stimulation that you might reach the calcium concentration a little bit like that. And then you'll trigger this amount of transmitter release, okay? In the second stimuli because they are so close in time, the calcium level will decrease because of the buffering, and the diffusion, and exclusion mechanisms. But the calcium level actually did not completely go back to the total baseline level. You still have a little bit of calcium left, okay. And then we are stimulating for the next pulse while you are going to trigger the same amount of calcium influx. Just like at the beginning. But because you already have some leftover so called residual calcium, okay, residual. Your total calcium level actually is increased slightly because of this non-linear relationship between calcium and transmitter release. While one observe will be a higher amount of transmitter work and release. So this is due to the presynaptic more calcium and more transmitter release, okay. And in some synapse, okay. Again, this is how the diversity of nervous system. If you have relative high frequency stimulation, okay, rather than a pair what you observe is the stimulation over time. Actually you got the response decrease, okay. So, this is called depression and in this short term is called short term depression, okay. This illustrate that over the stimulation the response will go lower and lower, okay. What may cause this reduction of the synaptic response in your opinion, okay? That's one possibility, right? Because we're stimulating the nerve at a high frequency, 50 hertz or even higher, okay. So, at that time you're triggering pretty intense, transmitter release, right? And then this vesicle will dump, all over the counter. And then, another one will dump its content. The region reaching of the vesicle through that recycling process, is slower than the speed to release those transmitters, okay. And therefore, in the second part, in the later part, the release may become smaller and smaller, okay. And the prediction will be, in that case you wait, you don't stimulate you wait. Some time later it will recover and then stimulate it again. And then you will see the recovery of the response. In the postsynaptic cells that can sense the presynaptic releasing of the transmitter. All of those are synaptic responses, so they are recording from the postsynaptic cell. So that's another possibility. So this is the depression because of the vesicle depletion. So how a vesicle of poor depletion. Indeed, actually that's another neat mechanisms people found out related to calcium. People found that depends on the synapse. In a prisoner terminal, there is the voltage gated calcium channel, okay. And this voltage gated calcium channel is a very sophisticated machine. But in the only want it to open to allow calcium comes in, okay, some of this voltage-gated calcium channel. They are also inferenced by the intracellular calcium, okay. So they will depends on the condition. The calcium influx will cause this channel to inactivate [FOREIGN] okay. So it's as if that this voltage-gated calcium channel is self-sensing machine. It has the feedback assistant in itself, okay, once the calcium comes in. And it senses that, intracellularly all ready has a lot of calcium. I need to shut up, okay. So this can also, explained in some synapse. During the stimulation because the previous stimulation accumulate a lot of calcium that are not dissipated fast enough, okay. And those calcium will in turn inhibit the sensitivity of voltage-gated calcium channel to open in the same number of action potentials. And therefore, you have less calcium comes in. And because of the calcium determines the transmitter release, and that's transmitter release, okay. So indeed, to test a synapse, which mechanism occurred, you'll probably need to simultaneously measure the amount of transmitter release and the calcium level, okay. To attribute how much is from the calcium in activation and how much is due to the depletion of the vesicle pool, okay. And actually not that many synapse have been that well studied. As we'll know, the different synapses have different personalities. They might have different mechanism in work. And different voltage-gated calcium channel, they also have different sensitivity to the calcium-induced in activation.
