So lets talk a little bit more abotu the Neurotrophins, the neuro receptors. So that we know that there is a family of neurotrophins now, the most famous and a first discovered neurotrophin was Nerve Growth Factor, NGF, but we've since identified at least three other neurotrophins. There is an important molecule called. Brain derived neurotrophic factor, BDNF. there are other neurotrophins that we call NT-4/5, and NT-3. So these all bear some structural similarity, and their mechanisms of actions also are similar. The neurotrophins interact with a set of receptors. That have tariceen cynaise activity on the cytoplasmic surface. So we call these TRK or track receptor's for short. So track A receptor interacts with nerve growth factor. The track B receptor interacts with BDNF and NT-4/5. And the track C receptor interacts with Neurotrophin three. Now what are the consequences of receptor activation? Well, the consequences are incredibly diverse. And as is usual for receptors that engage metabolic processes The impacts of receptor interaction with its ligand can be as diverse as the second messenger systems that are present in that neuron. And this is the case for our tract receptors. There are tract receptors that interact with various kinds of signaling pathways. I won't go through the details of each. But I'll just make the point that the distinctions among these second messenger pathways are what accounts for the differential effects of neurotrophins. Some neurotrophins will effect specifically cell survival. Others will work through a variety of pathways that mediate activity-dependent plasticity. And the capacity to respond to coordinated patterns of electrical activity. Other neurotrophins mediated pathways will have a more restricted affect on the survival of individual neuri /g, that is individual axon collateral's, or dendritick branches Or some of these pathways might influence the transcription of genes that allow for the further differentiation of the neuron. Well, these neurotrophins and their receptors are, are a picture of, the signaling that takes place after these neurotrophins have been processed. and differentiated through a post transitional modification. But before that happens, these Neurotrophins interact with anohter receptor that we call the P75 Receptor. So the P75 binds to the Relatively unprocessed forms of these neurotrophins that are synthesized and released. The processing happens after they're released and as they interact with enzymes and proteases that are present in the extra cellular spaces. This P75 receptor Interacts with the relatively unprocessed form the neurotrophins which is what we find when they're newly released into the extra cellular spaces. there after they can be processed and cleaved in various ways, modified by enzymes and perdiasus and are either bound to the surface of membranes or present in the extra cellular matrix. The consequences of P75 activation likewise can be diverse. one can impact the growth in axons and dendrites. One can impact either promoting the survival of the cell or activating the genes that result in the death of the cell, through the process of apatosis. So, again diversity of second messenger systems, as a consequence of the interaction of the neurotrophin and its receptor. Now some of these neurotrophin effects are actually taking place in the cytoplasm and even in the nucleus and the neurons. So there must be some means by which the signal can Process in the retrograde direction from the growth cone, or the developing synapse, back to the cell body. So how does that happen? Well we now have a, a increasingly detailed understanding of how the neurotrophin and its receptor can become internalized. And then associated with the transport machinery that allows that internalized structure to be shipped back to the cell body, where the neurotrophin and its receptor can mediate additional impacts on the growth and differentiation of the neuron. Well this can happen as neurotrophin interacts with its receptors. And this complex then engages a set of scaffolding proteins that can internalize this receptor complex. Forming an endozone that can then affiliate with a molecular motor. Along a microtubule network. That allows this complex to be translocated back to the cell body. And once in the cell body, then the receptor can engage other kinds of second messenger systems that may be present there, that can impact the growth and the survival of that entire neuron And finally today, I'd like to speak to you about the molecular mechanisms that are beginning to be understood that are responsible for the formation of synaptic connections. Well, this begins when a presumptive pre-synaptic element is recognized by some post-synaptic target site. And there are calcium dependent adhesion molecules, our cadherins and protocadherins, that seem to be responsible for this early recognition event. And following the interaction of these adhesion molecules, the early differentiation of the presynaptic and postsynaptic elements begins to take place. So it's very likely, as a result of activation of these adhesion molecules, that we begin to see the formation of vesicles. And the machinery that will become essential for processing these vesicles in the presynaptic terminal. Well, as the process ensues and additional specialization begins to be induced at that pre-synaptic site, we know that a number of other factors become very important. And we begin to see the assembly of a network. Of inductive signals that begin to influence the construction of the pre-synaptic side of the synapse, which involves the formation of an active zone. And all the metabolic machinery that I hopeful, hopefully you will recall from our studies of neural signaling in unit two. As well as the construction of the postsynapatic side of the synapse, which involves the assembly of ion channels, and second messenger systems, and the organization of a post-synaptic scaffold that will allow for the trafficking of receptors to that postsynaptic membrane and away from it. Well, we know something now about some of the molecules that are involved. There are additional families of cell adhesion molecules that are important. Ephrin signals become important. And one very important substance that seems to have an early impact on this stage of maturation is called neuroregulin. Well, all these factors are operating here at this complex of proteins, and let's take a closer look at that. So here is neuregulin, which is a pre-synaptic protein that can be released and can diffuse into that post, that presumptive post-synaptic cleft. Where it can begin to serve as an inductive signal, which begins to assemble all these proteins that are important for setting up that post-synaptic site. Eventually, two other molecules become very much involved. One called neurexin on the pre-synaptic side and neuroligin on the post synaptic side. On the pre-synaptic side, neurexin is important for beginning to build up this active zone, where synaptic vesicles begin to interact with snare proteins, and other important proteins, including synapto tagmin. Which is that molecule that detects the presence of presynaptic calcium. One also needs to cluster voltage gated calcium channels near this active zone, such that calcium influx can be local, and it can be rapid, leading to the development of a fusion pore. And the exocytosis of the contents of the synaptic vesicles. Well all of this machinery needs to be aggregated and organized in a coherent way for the formation of a viable presynaptic element. Neurexin seems to be an important signal that induces this organization. On the postsynaptic side neuroligin does complementary functions aggregating the protein complexes that are essential for the insertion of appropriate receptors. Such as our AMPAR receptors for glutamate or our NMDA receptors. As well as providing for the aggregation of postsynaptic density proteins that are critical for the proper trafficking of these receptors up to that postsynaptic membrane, or their withdrawal from that membrane. In addition, there are second messenger systems that become affiliated. With various types of receptors, as you now know. And all of this has to be orchestrated in a way that allows for the post synaptic cell to respond to the chemical message released by the presynaptic element. So this is a progressive series of events that are mediated via inductive signals that operate. Over a time course that establishes the structure and function of the mature synaptic connection. So, before we conclude this tutorial, I'll leave you with one final study question that will hopefully focus your attention on neurotrophins and the important role they play In mediating the establishment of proper connections in the developing nervous system. So I'll see you next time and I'll have the privilege of sharing with you some of the research work that I've been involved with together with my collaborators over the years. And I'll have a chance to talk to you about one of my favorite topics which is the influence of experience in shaping the structure of neural circuits in the developing brain. I'll see you then, thanks for listening and hope you enjoy your studies of neural development.
