This is the structure of hippocampus, that we talked before when we talk about LTP, long term presentation. So now we'll use LTP, as another example not talking about anatomy, the importance of anatomy in biological study but also the signaling, the different signaling pathways, the importance of different signaling pathways in one biological of functions. LTP, so let's go through this again so the requirements of LTP generation is activation of synapses. And then the strong depolarization at the post-synaptic sites, and then for hippocampus CA1 region LTP to be induced. We need a post-synaptic depolarization activation of NMDA receptors, one glutamate receptor and the influx of calcium ions and activation of this calcium ion on several second messenger systems in post-synaptic cell. So for LTP, we can have so-called early LTP or late LTP. Early LTP, normally lasts only hours, several hours. And late LTP last at least 24 hours, one day. So for early LTP, it doesn't require new protein synthesis, but for late LTP it requires new protein synthesis. RNA synthesis and sometimes the structure change of the neuron. So this is the control, this is the presynaptic side, here is the post synaptic side, these are synaptic vesicle containing glutamate, the excitatory neurotransmitter. And then these glutamate vesicle, move towards the presynaptic membrane and it gets released into the synaptic cleft region. Glutamate will bind to the glutamic receptor at the post-synaptic membrane. These receptors include AMPA receptors or metabotropic receptor, glutamate receptors. Also there are special kind of receptor called NMDA receptor. Glutamate will bind to NMDA receptor as well. For the AMPA receptor, after glutamate binding, The AMPA receptor itself is an ion channel. So, the AMPA receptor will let sodium channel flow into the cell. Potassium channel flow outside of the cell. So, we will depolarize the postsynaptic membrane. But for the NMDA receptor, the glutamate will bind to NMDA receptor, but inside of the NMDA receptor, this yellow thing, there is a magnesium ion blocking the NMDA receptor channel only when the post synaptic membrane, the depolarization of the post synaptic membrane reach certain value that the blockage of this magnesium ion will get removed and NMDA receptor will be open. So, NMDA receptor is a voltage dependent receptor ion channel. So for the early stage of LTP, this part here, so for early stage of LTP. Because we have both trains, high frequencies stimulations after the presynaptic side. So, lots of glutamate get release into the synaptic space into this synaptic cleft area. So lots of AMPA receptor are activated, leading to the post synaptic membrane potential reached certain value. Depolarization, reached certain value, so that the NMDA receptor are open. The NMDA receptor are calcium channels. The opening of NMDA receptor leads to the influx of calcium ions. So, the calcium gets into the postsynaptic site. And then the calcium ion will activate a protein called calmodulin. This calmodulin can act as a second messenger. Will further activate PKC pathway, tyrosine kinase and then what happened here is the long time enhancement of the postsynaptic response. So, this is the mechanism, local molecular mechanism for early LTP happened here. And if this process last longer, that calmodulin can go back into the cell body and go into the nucleus,it would activate CREB. CREB or bind to the tree element uncertain DNA sequence and then will start the DNA or regulate to the DNA expression or make new proteins. And then this new proteins will go this new proteins include more AMPA and more NMDA receptors. And these newly synthesized protein will be transported to the spines to make new receptors at the post synaptic side. And even this newly synthesized protein can be transported into a long the dendrite and make new synapses, so in the long form or in the late stage of LTP, we have new protein synthesized. We have new receptors synthesized by the nucleus and also we have the growth of appearance of new synapses. So the LTP can last even longer for days, so this molecular process under either early LTP or late LTP are quite different. But both of them requires neurotransmitter release, the binding of neurotransmitter and the post-synaptic receptors the effect of second messenger, the effect of ions influx to the cells and then the gene transcription after the second messenger and then the new protein synthesize and the localization. So the LTP, both early LTP, and late LTP are good examples for lots of signaling transductions process happened in the cell. The mechanism for early LTP are the single train stimulation, or high-frequency stimulation, will make depolarization of the postsynaptic membrane. And this depolarization will remove the blockage of magnesium ions of the NMDA receptor. So, the NMDA receptor now are activated and then NMDA receptor are calcium channels. So when NMDA receptors are open, the calcium get inflexed into the post synaptic cells and it will further activate the downstream protein kinase including calmodulin and PKC pathway, and in this in fact, this activated change of AMPA receptor. And this will further change activation of AMPA receptor. The AMPA receptor itself, is the sodium and potassium channel will make the influx of sodium ions. So, this continuous increase of sodium influx or make a prolonged enhancement of synaptic transmission. So, that's the mechanism of early LTP. And for late LTP, if we stimulate cells for or brain slices for a long time, we'll again have depolarization of postsynaptic membrane. This will remove the blockage of magnesium ions of NMDA receptor. And then calcium will get into the postsynaptic side. And then calcium will activate calmodulin, calmodulin will through AC pathway and then activate cAMP. cAMP will activate MAP kinase. MAP kinase, phosphorylate CREB, and then CREB get into nucleus, bind to the responsible element, the CRE. And then CRE, will make the DNA synthesis, will make the regulation of DNA expression, will express new proteins that are necessary for the formation of new synapses. So, this is the mechanism for Late LTP.
