FUNDAMENTALS 1: 10:00-11:00SCRIBE: KRATIKA PAREEK

9/20/2010PROOF: ANGI GULLARD

THEIBERT NEUROTRANSMITTERS PAGE 1 OF 11

I.NEUROTRANSMITTERS [S3]

  1. Neurochemistry is thought to be a subdivision of 2 different types of specialties. They include biochemistry and neuroscience. Neuroscience has to do with the brain, PNS (peripheral nervous system) and the spinal cord.

i.Signaling between neurons is a very special type of cell – cell signaling. One thing that specializes them is the type of chemicals that are used for signaling and these include the neurotransmitters and the neuropeptides as well as the speed and the specificity of the signal.

ii.Today we are gonna talk about synaptic signaling, which is a type of paracrine signaling where the signaling takes place between 2 different neurons or between a neuron or its target cells and this happens in the synapse.

iii.Acetylcholine was the first neurotransmitter to be identified by Otto Loewi. He isolated Ach from a specific preparation and showed that it could regulate the activity of the heart. He won the Nobel Prize for the discovery of Ach.

II.Outline [S4]

  1. First talk about nervous system and kinds of cells that make it up.
  2. Ion channels involved in action potential and synaptic signaling.
  3. Morphology and function of pre-synaptic and post-synaptic area.
  4. How neurotransmitters are made
  5. Post-synaptic response and receptor proteins involved
  6. Diseases

III.Review of nervous system and neurotransmission [S5]

  1. Two main types of cells comprise the nervous system  neurons and glial cells. Glial cells glue their neurons together, metabolic support, removing toxins and small molecules and myelination and immune function.
  1. Synaptic signaling uses neurotransmitters, but it’s a lot more specific because synapses are regions where neurons are close together, specific because there are very specific receptors, and synaptic signaling is very rapid and neurons can communicate with each other in milliseconds.
  2. Nerve cells are highly polarized cells. They have a cell body, which contains the nucleus, protein synthetic machinery. This is where the majority of proteins and mRNA are synthesized.
  1. It also has 2 regions of specialization: dendritic regions  long thin processes, which are the info receiving part of a neuron. Other neurons make contact with these dendrites at the synapse. Typically neurons have a lot of dendrites. They are highly branched and this is called dendritic arborization. Dendrites also have dendritic spines signaling at synaptic spines is the major place where excitatory transmission takes place between neurons.
  1. On the other side is the axon. It’s the info sending part of the neuron. Typically neurons have 1 axon, but it can branch at the end and produce the axon terminal.
  1. So the flow of info is from the dendrites or the cell body to the axon.
  1. Speed of synaptic transmission is determined by myelination. Majority of neurons in the PNS have a specific insulation called myelin. It speeds up the conduction ofsynaptic signaling and also allows for more efficient signaling. Some of the neurons in the CNS (central nervous system) go through the white matter. This is where the axons of the brain have their myelin sheaths.

IV.Central nervous system [S6]

  1. There are 2 main parts of the nervous system: CNS = brain and spinal cord and the PNS = sensory neurons and the projections (axons) from the motor neurons.
  1. PNS is involved in gathering, collecting, and detecting sensory kind of information such like heat, light, pain, and the axons will then transfer this info into the spinal cord or the brain. CNS then integrates that info, stores it, and the brain will decide to generate specific behavior. Behavior is performed by the motor neurons in the form of muscle contraction.
  2. There are many different kinds of neurons that make up the different divisions of the CNS and the PNS and the types of signaling is well- conserved.
  1. Talk about how neurons communicate with their target cells, what neurotransmission is and what are some of the neurotransmitters and how they perform their function.

V.Different kinds of neurons and their morphology [S7]

  1. The 2 major types of neurons in the PNS are sensory neurons and the axons and projections of motor neurons.
  1. Cell bodies of motor neurons lie in the spinal cord. So the motor neurons are a part of both the CNS and the PNS.
  2. The motor neurons project their axons to 2 different types of targets. One is muscle cells, and they can innervate and form contacts and signals to skeletal, cardiac, and smooth muscle. Motor neurons can also regulate glands and so they can control secretions of other cells and they are found in the PNS.
  3. So this is info being sent from the brain to the rest of the body.
  1. Sensory neurons gather info from different parts of the body and send it to the CNS.
  2. Other neurons found in the brain and the spinal cord are called interneurons. There are many different kinds of these.
  1. They can be found in the cortex, the cerebellum, hippocampus, throughout the spinal cord.
  2. They receive info from the sensory and other neurons, integrate this info and generate behavior by synapsing on motor neurons and allowing for the info to flow that way.
  1. The neurons in the PNS are myelinated because they are often very long and they have to have this myelination in order to have rapid and efficient conduction.
  2. Many of the neurons in the CNS are myelinated, but are not either.

VI.The conduction properties of nerves [S8]

  1. So I’m gonna give an overview of what I am going to talk about today, and this is the essential core of what you need to know about synaptic transmission.
  2. Drawing on the board  neurons use electrical signal called the action potential to send info to their target cells.
  1. Action potential is a way of depolarization followed by repolarization.
  2. Action potential travels down the axon. It’s generated at the axon hillock because this is where the voltage-gated sodium channels are concentrated and this is what begins the action potential.
  3. Action potential travels down the axon until it arrives at the pre-synaptic region (before the synaptic region).
  4. When the action potential arrives at the pre synaptic terminal, the electrical signal gets converted to a chemical signal. This occurs in 2 ways.
  5. First there is an activation of calcium influx into the pre-synaptic terminal. This signal is sensed by proteins present on vesicles called synaptic vesicles, which contain high concentrations of neurotransmitters. So you have pre-packaged neurotransmitters in these vesicles found concentrated in the pre-synaptic region.
  1. The influx in calcium then instructs these vesicles to fuse with the pre- synaptic plasma membrane and they release their contents in the region between the 2 cells called the synapse.
  2. The synapse is a very small space about 20 nm in diameter. A synaptic vesicle is about 40-50 nm. It’s very close to the post-synaptic membrane, but the 2 membranes are not fused. So the signaling that takes place between these 2 cells has got to occur through neurotransmitters.
  3. The vesicles fuse and this allows the neurotransmitters to be put into the synapse. They bind to specific receptors on the pos synaptic cells. These receptors mediate changes in the postsynaptic cells, which then mediates the synaptic transmission.
  4. There are 2 different types of receptors: receptors which directly activate changes in the electrical properties of neurons, and there are neurons which are involved in producing 2nd messenger through G-proteins.
  5. This info then can lead to electrical changes in the dendrite, which are transmitted passively along the dendrites. There can be 1000s of different inputs at the neuron and at the axon hillock all of these inputs are summed. Some can be excitatory or inhibitory and if the summation allows for large enough depolarization this neuron will then fire an action potential.
  6. So these are the main parts of an action potential that you are going to need to know.
  1. So I’m going to start talking about action potentials. The resting membrane potential in most cells is -60 to -70mv. It’s negative on the inside with respect to the outside.
  1. If that membrane potential becomes more positive up to about -50 or -55mv, and if that cell is an excitable cell i.e. it has voltage-gated ion channels, that cell will be able to fire an action potential.
  2. An action potential is an all or nothing wave of depolarization of the plasma membrane. What happens is when the membrane potential becomes more positive, it activates an increase in sodium permeability first, followed by an increase in potassium permeability second.
  3. These are caused by the specific set of ion channels found at the axon hillock and also the length of the axon.
  4. The resting potential changes due to some inputs that the neuron is receiving that leads to this very large depolarization and the membrane potential goes up to +30 and then the membrane repolarizes and it actually repolarizes past the resting potential. This is called hyperpolarization and then the cell goes to normal.

VII.Mechanism of action potential [S9]

  1. So what is the mechanism that underlies an action potential? It turns out that it is carried by 2 different types of voltage gated ion channels.
  1. The initial depolarization is by the activity of voltage-gated sodium channels, which are found in the axonal plasma membrane.
  2. At rest, the voltage-gated sodium channels are closed. When they hit threshold to get to about -50 to -55mv, this change in membrane potential is sensed by specific protein channels within the core of the channel.
  3. This leads to the opening of voltage-gated sodium channels. Remember that the sodium potassium ATPase keeps the concentration of sodium high outside and low inside.
  4. So once you open this channel, sodium then flows down its electrochemical gradient and flows into the cell, and the cell becomes more and more positive. It becomes even more depolarized.
  5. Eventually this channel becomes inactive and it closes and it stays closed for a refractory period until the membrane goes to the resting membrane potential.
  1. Now subsequently, there is an activation of voltage-gated potassium channels. The sodium potassium ATPase keeps the concentration of sodium high inside the cell and low outside.
  1. So after the depolarization this leads to the activation of voltage potassium; potassium goes out and membrane repolarizes back to the resting potential.

VIII.Structure and operation of ion channels [S10]

  1. Ion channels are selective.
  1. They only allow specific ions to flow through them. Sodium channel is specific for sodium. Potassium channel is specific for potassium.
  2. Potassium channels are slower than the sodium channels and they are said to be delayed, and that’s why there is an initial depolarization followed by the repolarization of the membrane.
  1. A lot of what we know about these voltage-gated channels was facilitated by the use of specific toxins, which have been identified to block these channels.
  1. Two different types of toxins are tetrodotoxin from puffer fish and saxitoxinfrom amoebas; they have been shown to block the sodium channels.
  2. The result of this is that because the neurons in their prey are unable to fire action potentials because their sodium channels are blocked, these cells are unable to release their neurotransmitters and they cannot perform muscle contraction and this leads to paralysis of their prey.
  3. It’s kind of interesting how no specific potassium channel blockers have been identified from different vertebrate or invertebrate species.
  1. Now let’s look at a segment of an axon.
  1. Here is an action potential, which is being conducted by an increase in sodium permeability and is being carried down the axon looking at time 0.
  2. If we look at after a millisecond, we see that the action potential has been carried to the next segment of the axon and now there is influx of sodium, and this leads to depolarization of the membrane. Subsequently, you get an activation of potassium channels, and this leads to repolarization and hyperpolarization.

IX.Looking at the action potential in motion [S11]

  1. The action potential only travels in 1 direction along the axon and the reason for this is because there is a refractory period after which sodium channels are inactivated. They cannot be opened again until the membrane potential returns to its resting membrane potential. And this guarantees that the action potential only travels unidirectionally down to its pre-synaptic membrane.

X.Myelination: what is it and what it does [S12]

  1. Myelin is specific lipid membrane made by Schwann cells in the PNS and by the oligodendrocytes in the CNS.
  1. These glial cells produce this membrane, which can wrap around its axons and lead to its insulation.
  2. This is critical because this insulation allows for very rapid conduction of the axon, and it is very efficient.
  3. Neuronal axons are leaky and so ions can leak across the membrane and insulation prevents the leakiness of these axons.
  1. Myelin has been very well characterized. We know all of the lipids and proteins.
  1. There are specific de-myelination diseases like multiple sclerosis where we make auto-antibodies to myelin proteins and this leads to decrease in myelin and that can reduce conduction velocity along specific axons. Motor neurons are very badly affected in multiple sclerosis because they are so long.

XI.Myelinated nerves have the advantage...[S13]

  1. So what does myelin do?
  1. Myelinated nerves can carry action potentials 10x times faster than unmyelinated nerves.
  2. This is very critical because the rate of conduction of an action potential is proportional to the diameter of the neuron. If neuronal axons were not myelinated, then we would need neurons with large diameters to take the action potential to the periphery at the rate at which we need them, especially for things like escape responses.

XII.How myelinated neurons work? [S14]

  1. Myelination creates a problem because you have created a barrier to the flow of ions across the membrane.
  1. The way that neurons get across this is by having gaps at specific regions in the neurons. These are called nodes of Ranvier. Here the plasma membrane has direct access to sodium and potassium ions flowing across the membrane.
  2. Because of this reason conduction of action potentials in myelinated axons is called saltatory.
  3. What this means is that you have specific regions where there are concentrated voltage-gated sodium and potassium channels where there is activation of these channels at these unmyelinated gaps, and sodium and potassium can flow in and out.
  4. Then you have a passive flow of sodium and potassium down the axon of concentrated regions of voltage-gated ion channels, which can then be activated.
  5. So you have a jumping of action potentials from the nodes of Ranvier.

XIII.The pre-synaptic area [S15]

  1. The action potential is travelling down the neuron. It’s an electrical way. So what is the purpose of this?
  1. The reason that action potentials are so important is that they will allow transmission of info from one nerve to its target cell, and the way it does this is through synaptic transmission.
  2. I will talk about the pre-synaptic region as the region where transduction takes place, the synthesis of neurotransmitters in this region, and then the mechanism of neurotransmitter release.

XIV.The pre-synaptic area is a very busy...[S17]

  1. Pre-synaptic area is part of the axon and this can be viewed morphologically as pre synaptic to the synaptic region. It’s highly enriched in synaptic vesicles.
  1. These pre-synaptic vesicles have to be loaded up with neurotransmitters before they can be released. They are generated from the early endosome in a cycle, which allows them to be filled up with neurotransmitters.
  2. When the action potential arrives at the pre-synaptic terminal, it activates voltage- gated calcium channels in the pre-synaptic membrane.
  1. The voltage-gated calcium channels are activated by the depolarization that is brought by the action potential.
  2. In addition to the sodium and potassium gradient, there is also a high concentration of calcium gradient outside the cell.
  3. You open up the voltage-gated calcium channel, and calcium flows down its concentration gradient and into the pre-synaptic neuron.
  4. Once the calcium gets in there, it stimulates the fusion of synaptic vesicles with the pre-synaptic plasma membrane.

XV.Figure showing what she talked about in the previous slide [S18]

XVI.Arrival at the synapse [S19]

  1. Before I talk about what some of the mechanisms are for the vesicles fusing, I wanna talk about neurotransmitters.
  1. Neurotransmitters are a type of chemical that are specific in synaptic signaling.

XVII.The synthesis of neurotransmitters [S20]