 We know that it is said that the more we repeat a certain thing, the more we remember it, isn't it? That's why we used to call A for Apple, A for Apple so many times in our childhood. So basically repetition or revising things increases the memory of that learning. So why is it so? Well, the basis for is it long-term potential. So long-term potential says that due to repeated firing of a presynaptic neuron and due to the release of the neurotransmitters, basically increased the release of the neurotransmitters which occur when the presynaptic neuron is repeatedly firing, there will be increased response from the postsynaptic neuron. There will be increase in response and when we talk about response, basically we are talking about the increased voltage change in the postsynaptic neuron that is increased EPSP which ultimately will lead to increase in the number of the action potentials. So whenever the amplitude of EPSP increases, the frequency of action potential increases in the postsynaptic neuron. So in simple terms, repeated firing of the presynaptic neurons will increase the postsynaptic response. So let us see what is the mechanism of long-term potential. See, the fundamentals of synaptic transmission we know that whenever there is action potential in the presynaptic neuron, it causes a release of the neurotransmitters, right? It causes a release of the neurotransmitters in the synaptic left and it acts on the postsynaptic neuron. It combines to certain receptors on the postsynaptic neuron and if it is an excitatory neurotransmitter, it leads to generation of EPSP. If EPSP reaches to threshold, it leads to generation of action potential and these two events are happening in the postsynaptic neuron. Now, when we talk about long-term potential, we are telling repeated firing. So this is the keyword, repeated firing of the presynaptic neuron and whenever there is repeated firing, each action potential is going to release more and more neurotransmitters and for long-term potential, the neurotransmitter involved is excitatory neurotransmitter Glutamate. This Glutamate has two types of receptors on the postsynaptic neuron. So one of these are AMP receptors, AMP receptors or ampereceptors and the other ones are NMDA receptors. So let us make another receptors, NMDA receptors. So this Glutamate can bind to both the receptors, right? So Glutamate binds to ampereceptors and NMDA receptors. So see, these NMDA receptors are actually blocked by magnesium ions. So these do not open. Instead, it is the ampereceptors which open and due to opening of ampereceptors, there is entry of sodium ions causing generation of EPSP. So this is normally happening but with the increased release of the neurotransmitters, what happens that more ampereceptors will open and more sodium ions will enter into the postsynaptic neuron and because of increased EPSP that is more voltage change, it will throw off magnesium ions from the NMDA receptor. So this block of the NMDA receptor is overcome by means of the voltage change. Increased voltage change, magnesium will move out and you know the Glutamate is available. So it will also bind to this NMDA receptors and these NMDA receptors allow entry of calcium ions. So once they open, there is entry of calcium ions. So ampereceptors cause the entry of the sodium ions which leads to EPSP and NMDA receptors cause entry of calcium ions. Now because of the entry of the calcium ions, there are certain downstream changes within the postsynaptic neuron. What are these changes? Calcium basically binds with a calcium binding protein that is calmodulin and this in turn leads to activation of calcium calmodulin pathway. Calcium calmodulin pathway in turn activates calcium calmodulin kinase which will cause the phosphorylation of the ampereceptors. So this is important phosphorylation of ampereceptors. Plus there is also activation of other pathways which leads to more insertion of ampereceptors on the presynaptic neuron. So what we saw here, here, so we drew very less receptors. Due to increase in calcium, the number of the ampereceptors here are going to increase and due to the phosphorylation of the receptors, the conductance of the ampereceptors is increased. So number is also increased and whatever was available, there will be increase in conductance so that more sodium ions can enter through the same channels. So what is happening basically? The same neurotransmitter will now lead to increased response in the postsynaptic neuron. So that is one mechanism of long-term potentiation. There are other things also which are happening. One is release of a gas that is the nitric oxide from the postsynaptic neuron and this gas causes changes in the presynaptic neuron such that with each action potential, now there will be increased release of the neurotransmitter as well. So there are changes in the postsynaptic neuron and there are changes in the presynaptic neuron as well. Third, there is phosphorylation of transcription factors as well and this causes changes at the genetic level causing increase in the synthesis of proteins and with increase in the synthesis of proteins, there will be formation of more synaptic connections with the same neuron. So there are dendrites, right? So they will form more synaptic connections with the same neuron such that the EPSP will now be generated in these dendrites as well and there are high chances of EPSP to reach to the threshold and to be maintained at high level for a longer time, isn't it? So that action potential can be maintained. And here was repeated firing because you see only when repeated firing will happen, there will be increased release of the neurotransmitter which can bind amper receptors such that the EPSP reaches to that level so that the magnesium block of the NMDA receptor is removed. So quickly maybe revise this using a flow chart. So I will leave you with this flow chart. What it says? With repeated firing, glutamate released from presynaptic neuron means to both the receptors on the presynaptic neuron but only the amper channels open due to which there is sodium entry which causes depolarizing, depolarizes the presynaptic neuron and sufficient depolarization. So there should be adequate amount, critical amount of depolarization should be there such that the magnesium block from the NMDA receptor is removed and this opens the NMDA channels causing calcium entry. Then because of calcium entry, there is activation of the second messenger's pathway in the post-synaptic neuron. This will make changes in the presynaptic neuron as well as the post-synaptic neuron. So in the post-synaptic neuron, there will be insertion of more amper channels in the post-synaptic membrane plus phosphorylation of the amper channels will cause increased conductance and hence increased sensitivity of the post-synaptic neuron to glutamate. Then in the post-synaptic neuron, there will be constellation of the transcription factors so that the new synaptic connections can grow and in the presynaptic neuron, there is some retrograde changes also. So there is release of nitric oxide which enters into the presynaptic neuron and this causes increased glutamate release by the presynaptic neuron and all these events cause persistently more EPSPs and action potential. So every time we don't want repetition, right? For some time when there is repeated firing of the presynaptic neuron, later on because of increased sensitivity with a single action potential also, there will be persistently more EPSPs and action potentials. Thanks for watching the video. If you liked it, do press the like button, do share the video with others and don't forget to subscribe to the channel Physiology Open. Thank you.