Neurotrophin Receptors and Synapse Formation

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Medical Neuroscience

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Duke University

Medical Neuroscience

1149 classificações

Medical Neuroscience explores the functional organization and neurophysiology of the human central nervous system, while providing a neurobiological framework for understanding human behavior. In this course, you will discover the organization of the neural systems in the brain and spinal cord that mediate sensation, motivate bodily action, and integrate sensorimotor signals with memory, emotion and related faculties of cognition. The overall goal of this course is to provide the foundation for understanding the impairments of sensation, action and cognition that accompany injury, disease or dysfunction in the central nervous system. The course will build upon knowledge acquired through prior studies of cell and molecular biology, general physiology and human anatomy, as we focus primarily on the central nervous system. This online course is designed to include all of the core concepts in neurophysiology and clinical neuroanatomy that would be presented in most first-year neuroscience courses in schools of medicine. However, there are some topics (e.g., biological psychiatry) and several learning experiences (e.g., hands-on brain dissection) that we provide in the corresponding course offered in the Duke University School of Medicine on campus that we are not attempting to reproduce in Medical Neuroscience online. Nevertheless, our aim is to faithfully present in scope and rigor a medical school caliber course experience. This course comprises six units of content organized into 12 weeks, with an additional week for a comprehensive final exam: - Unit 1 Neuroanatomy (weeks 1-2). This unit covers the surface anatomy of the human brain, its internal structure, and the overall organization of sensory and motor systems in the brainstem and spinal cord. - Unit 2 Neural signaling (weeks 3-4). This unit addresses the fundamental mechanisms of neuronal excitability, signal generation and propagation, synaptic transmission, post synaptic mechanisms of signal integration, and neural plasticity. - Unit 3 Sensory systems (weeks 5-7). Here, you will learn the overall organization and function of the sensory systems that contribute to our sense of self relative to the world around us: somatic sensory systems, proprioception, vision, audition, and balance senses. - Unit 4 Motor systems (weeks 8-9). In this unit, we will examine the organization and function of the brain and spinal mechanisms that govern bodily movement. - Unit 5 Brain Development (week 10). Next, we turn our attention to the neurobiological mechanisms for building the nervous system in embryonic development and in early postnatal life; we will also consider how the brain changes across the lifespan. - Unit 6 Cognition (weeks 11-12). The course concludes with a survey of the association systems of the cerebral hemispheres, with an emphasis on cortical networks that integrate perception, memory and emotion in organizing behavior and planning for the future; we will also consider brain systems for maintaining homeostasis and regulating brain state.

Na lição

The Changing Brain: The Brain Across the Lifespan

This module represents another turning point in Medical Neuroscience. Now that we have surveyed human neuroanatomy and our sensory and motor systems, we are ready to take a step back and consider how this magnificent central nervous system came to be the way that it is. We will also learn how the brain re-wires itself across the lifespan as genetic specification, experience-dependent plasticity and self-organization continue to interact, re-shaping the structure and function of neural circuits throughout the central nervous system.

Embryological Subdivisions of the Human CNS8:47

Major Forces In Early Brain Development12:36

Neurulation11:17

Formation of the Early CNS12:35

Inductive Signaling In CNS Formation15:10

Proliferation and Migration, part 117:23

Proliferation and Migration, part 210:59

Growth Cones11:42

Molecular Signals for Axon Guidance, part 113:22

Molecular Signals for Axon Guidance, part 212:36

Neurotrophins13:08

Neurotrophin Receptors and Synapse Formation11:43

Conheça os instrutores

Leonard E. White, Ph.D.
Associate Professor
Department of Neurology, Department of Neurobiology, Duke University School of Medicine; Department of Psychology & Neuroscience, Trinity College of Arts & Sciences; Director of Education, Duke Institute for Brain Sciences; Duke University

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.

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