Lecture 2 -Glial Cells no marg .pdf

Glial Cells -also known as "neuroglia" -find these cells in both the CNS and PNS -if you take a piece of neural tissue and count the number of cell sin the tissue, you find that for every neuron there are 50 glial cells in the tissue (50:1 glial:neurons ratio) far more glial cells in neural t...

Glial Cells -also known as "neuroglia" -find these cells in both the CNS and PNS -if you take a piece of neural tissue and count the number of cell sin the tissue, you find that for every neuron there are 50 glial cells in the tissue (50:1 glial:neurons ratio) far more glial cells in neural tissue than neurons glial cells are very important to the functioning of the nervous system during the last 30 years, we've started to look at glial cells and their functions in terms of the nervous system ◦glial cells play a central role in the development in neurodegenerative disease (Alzheimer's) these diseases are of glial cells - malfunctioning of glial cells slow these diseases down by understanding the glial cells, not just the neurons -in the CNS there are 4 types of glial cells: -these types of glial cells can be divided into subtypes that perform different functions Astrocytes ◦most numerous / common type of glial cell; most glial cells are astrocytes ◦called astrocytes because they have a lot of cell processes that extend from their cell body ‣ looks like a star ◦there are many subtypes of astrocytes ◦the functions that astrocytes carry out fall into 9 areas (9 functions) ‣ 1. synthesize and secrete neurotrophic factors (proteins that are involved in keeping neurons alive). one of the things that neurotrophic factors do is keep apoptotic mechanisms in cells from being turned on (keep them off). when apoptotic mechanisms are turned on, it kills the cell. Neurotrophic factors: signal neurons to differentiate during development ; they guide the development of the different neurons in different parts of the brain. not all neurons are the same, depending on what part of the brain they are in. these neurotrophic factors signal  differentiation (you become this type of neuron) synapse formation ; help to guide and form the synapses between neurons. if these neurotrophic factors are no longer produced, the synapse will break apart. it will not be maintained. they are not just active during the formation of the synapse, there is a continuous signaling. ‣ 2. Envelop the synaptic cleft and prevent neurotransmitters from diffusing outside of the cleft and contacting other neurons. isolate the synaptic cleft, when neurotransmitters are released they are held int he cleft and aren't allowed to diffuse out ‣ 3. they help remove neurotransmitters from the synaptic cleft after the target cell has responded. by helping to remove the NT, the action of the NT on the target cell is terminated so you don't get an overactive response form the target cell ‣ 4. provide physical support for the neurons of the CNS. there are no bones or cartilage int he CNS, so the physical support for the tissue is provided by astrocytes ‣ 5. regulate the extracellular concentrations of potassium. this regulation in the CNS is very important in the neuron's ability to maintain a stable membrane potential*. neurons have to have a stable membrane potential to elicit electrical signals ‣ 6. they are responsible for forming and maintaining the blood brain barrier (BBB). the BBB only allows certain substances to enter or leave the brain. serves to protect the CNS. EX: one of the things that the BBB does is regulates the amount of potassium allowed to move from the blood to the extracellular fluid (vise versa) in the CNS; how much K+ is allowed to enter or leave the extracellular fluid of the CNS the BBB also protects the CNS from toxins like heavy metals, pesticides, chemotherapy drugs (can't cross the BBB), bacterial endotoxins (can damage neural tissues) ‣ 7. they are involved in guiding the development of axons during embryonic development of the CNS. one of the things that makes the nervous system complex, in order for it to function properly, the correct connections have to be made (i can reach out and grab something with my hand). you have to have the correct connections made during  development. astrocytes guide this development, what they are to be, and where they go during embryonic development. ‣ 8. form scar tissue; if damage is done to the CNS, it stabilized the tissue and limits the spread of the damage ‣ 9. serve as a source of stem cells for the CNS; this is a new development that has been discovered recently. it has been discovered in some cases (particularly after damage) astrocytes can differentiate to become neural stem cells, which can then become neurons to help in recovery from damage -Oligodendrocytes wrap around the axons of neurons in the CNS this wrapping of the axons produces a covering called myelin more commonly referred to as the myelin sheath. electrically insulates the axons and increases the conduction velocity of the action potential along the axon by increasing the conduction velocity, signals can pass more quickly and you can process information faster -Microglia phagocytic cells that take up and digest cell debris if a neuron dies or starts to disintegrate, the microglia will digest and break it down phagocytose waste products produced by the neurons phagocytose pathogens that may invade the CNS -Ependymal Cells line the hollow spaces in the CNS called the ventricles your nervous system during the development, starts out as a tomb that has a hollow space in the center. the hollow space is maintained through development. they are called ventricles. the lining of the ventricles is made of these cells also secrete cerebrospinal fluid (CSF) some of this fluid seeps out onto the surface of the CNS. there are no bones or cartilages that  support the CNS. all the structures of the CNS float. the brain and spinal cord are not physically attached to the cranium or vertebral column 2 types of Glial Cells in the PNS -Satellite Cells perform analogous functions to the astrocytes of the CNS provide structural support, produce neurotrophic factors, form a BBB (not as good as the CNS) but regulates what is allows to enter the neurons of the PNS -Schwann Cells perform analogous functions to Oligodendrocytes in the CNS wrap around segments of axons in the PNS (create myelin sheath) and increase conduction velocity of action potentials in axons along the PNS Membrane Potential -all of the cells in your body have an electrical potential or voltage between the inside of the cell and extracellular fluid (ECF) -if we look at the electrical potential between the inside and outside cells, we find that the voltage or polarity is such that the inside of the cell is negative relative to the outside -the voltage or electrical potential is referred to as the membrane potential -the membrane potential originates from a combination of 3 factors (3 factors are combined to create the membrane potential) 1. a differential distribution of ions between the inside and outside of the cell ◦principle ions that are involved in the creation of the membrane potential; ‣ Sodium, or Na+, (positive charge of +1; most abundant ion in the extracellular fluids) ‣ Potassium, K+, (positive charge of +1; most abundant ion in the intracellular fluid - inside the cell) ‣ A- (anions: ions that carry a negative charge). primarily proteins and phosphate ions (phosphate found mostly inside of the cell - intracellular fluid) 2. the cell membrane is 40x more permeable to potassium (K+) than it is to sodium (Na+) ◦the cell membrane is impermeable to anions ◦if we look at the cell membrane, it has potassium leak channels, they are always open allowing potassium to flow across the membrane. what makes the cell membrane so permeable to K+* ◦there are no sodium or anion leak channels ‣ if you look at the distribution of these ions inside and outside the cell, you would find the concentration of potassium high inside the cell and low outside ‣ the concentration of sodium would be high outside and low inside ‣ the concentration of anions would he high inside and zero outside ◦because the cell membrane is highly permeable to potassium, and due to the K+ leak channels, the potassium ions are able to move down the concentration gradient from inside the cell to the outside. move from high concentration to low concentration ◦as these potassium ions are moving out, they are carrying positive charge with them. every K+ ion that moves out carries +1 with it. leaves behind the negatively charged anions inside the cell. not enough sodium inside to cancel out the negative charge. as the positive charge flows out, the inside becomes more and more negative ◦as a result, if we measure the voltage between the inside and outside of the cell, the inside of the cell is negative relative to the outside. ◦the movement of potassium through the leak channels down the concentration gradient will continue until the buildup of the negative charge inside the cell starts to attract positive potassium ions back in. the leak channels allow K+ to flow both out and in to the cell. ◦more negative the inside of the cell becomes, it starts pulling potassium ions back in through the leak channels. ◦eventually, a point is reaches where the electrical forces acting on the K+ ions to pull them back in, match the concentration gradient of the ions pushing them out. there will be a balance in the concentration gradient pushing K+ out. ‣ when this is reached, there is no net movement across the membrane ◦there is a balance, for every one pushed out, another is pulled in  ‣ the membrane potential at which this balance is established is called the potassium equilibrium potential ◦ the equilibrium potential for potassium is; Ek+ ◦because the movement of ions is governed by the physical laws of the universe, we can calculate the equilibrium potential for potassium using a formula that takes into account factors that act on ions ‣ Nernst Equation ; temperature is in kalvin ; R = gas constant ‣ used to calculate the equilibrium potential of an ion originally worked out using natural log (ln) Eion = RT/zF (ln ion extra / ion intra) Eion = 2.303 (RT / zF) (log ione/ioni) ‣ R = 8.31 jowles / mole / ºK) ***dont need to memorize arrows ‣ T= normal human body temp of 310 ºK ‣ z = charge the ion carries (potassium of +1) ‣ R = gas constant ‣ E= equilibrium potential ‣ F = 96,500 coulombs / mol RT/F = 26.72 mV 2.303 x 26.72 mV = 61.54 mV Eion = 61.54 mV / z ( log [iono] / [ioni] ) *** ione = extracellular charge ioni = intracellular charge ◦negative or positive sign tells you the polarity of the membrane potential ◦negative sign tells you that at EK+, -80mV, the inside of the cell (-80 mV on the inside relative to the outside) if the cell membrane were only permeable to potassium ions, the normal membrane potential would be equal to EK+ = -80 mV  in addition to being permeable to potassium, cell membranes are also slightly permeable to sodium (Na+) ◦there are no sodium leak channels, but some sodium will leak across the membrane ◦concentration gradient for sodium; sodium inside is 15mM and outside is 150mM ◦the equilibrium potential for sodium is + 61.5 mV ◦if the membrane were only permeable to sodium, if we measured the membrane potential, the inside of the cell would be +61.5mV inside relative to the outside of the cell the forces acting on the sodium ions pull sodium ions across the membrane. the membrane potential to the inside of the cell is normally negative relative to the outside positively charged ion is going to get pulled in by the negative inside charge concentration gradient is also pushing sodium across the membrane -electrochemical gradient acts on Na+ pushing inward across the membrane electrical : membrane potential and the negative inside charge chemical : concentration gradient -because the membrane is permeable to both potassium and sodium, the actual membrane potential (Vm) will be somewhere between the equilibrium potentials of potassium and sodium ◦somewhere between -80mV and +61.5 mV the membrane potential will be closest to the equilibrium potential of the ion (Eion) that the membrane is most permeable to ◦because the membrane is 40x more permeable to K+ than Na+, the actual membrane potential will be closer to the equilibrium potential of K (-80mV) than ENa. Goldman Equation -we can calculate the theoretical membrane potential of a cell using the Goldman Equation knowing the ions the membrane is permeable to and the concentration of these ions -just takes into account potassium and sodium ions: membrane is not permeable to other ions P = relative permeability of the membrane to the ion (potassium is 40 - 40x more permeable to potassium than sodium; sodium is 1)  if you calculate the Goldman Equation, Vm = -65mV the membrane potential of a cell should be about -65 mV according to the Goldman Equation negative sign on the membrane potential tells you the inside of the cell is negative relative to the outside ** Concentration Gradients for Sodium and Potassium (NA+/K+ ATPase pump) -maintained through an ion pump called the sodium-potassium ATPase pump -captures energy through the hydrolysis of ATP to move 3 sodium ions out for every 2 potassium it moves in ** not moving equal numbers across the membrane this pump is moving these ions against their concentration gradients move sodium from the inside to the outside (moving low conc to high conc) move potassium from outside to inside, moving it against the concentration gradient to move an ion against its concentration gradient, it takes energy -in addition to moving the ions across the membrane against their concentration gradients, the pump is moving more sodium out than potassium is coming in Na+ and K+ are both +1 the pump is moving more charge out than it is moving in the movement of more positive charge out than in contributes to the membrane potential the Goldman Equation does not take this pump into account *** taking this pump into account, the ACTUAL membrane potential is somewhat more negative than -65mV that the Goldman Equation predicts ** -The ACTUAL membrane potential for most neurons is about -70mV -this -70mV is referred to as the resting membrane potential it is called this because unless something changes (permeability, concentration gradients) this membrane potential is stable -the maintenance of a stable potassium concentration in the ECF around a neuron is very important for maintaining a stable membrane potential if the potassium concentration in the ECF were to increase, the increase of K+ in the ECF would  diminish K+ concentration gradient. as a result, the movement of potassium outward through the leak channels would be decreased. do not have the concentration gradient to push K+ through the leak channels across the membrane. ◦if you have less potassium moving out, you have more remaining inside the cell. this will influence the membrane potential and make it more positive. rather than being -70 it will be more positive. in order to maintain a stable membrane potential, you have to have a stable potassium ion concentration gradient in the extracellular fluids of the CNS -in the central nervous system, there are 2 things that work to maintain stable K+ concentration gradients one of the mechanisms that works to maintain stability is the blood brain barrier ◦BBB regulates the movement of potassium between the blood and extracellular fluids in the CNS, does not just allow K+ to flow in and out, maintains stability second mechanism: potassium spatial buffering ◦involves astrocytes -the ends of the cell processes (astrocytes) take up potassium from where its in high concentration, distributes it through the rest of the astrocyte, and into the extracellular fluid preventing local accumulation of K+ in ECF Gated Ion Channels -Neurons are unique in terms of cells, they have gated ion channels -these channels have little gates on them that can be opened and closed -when the gate is open, the ion that the channel is specific for is allowed to move through that channel as the ion moves through the channel, it is going to carry charge across the membrane, which is going to influence the Vm at that site in the neuron neurons use these types of gates channels to generate electrical signals -if the Vm is at a potential other than -70mV (resting membrane potential), then the ion will move across the membrane in the direction that will move Vm towards its equilibrium potential. if the gated ion channel is open on the neuron, the permeability for the ion is increased. this will allow for more potassium to flow OUT of the neuron. ◦if we add a gated K+ channel and open the ate, more K+ will be able to flow out if I allow more potassium to flow out, the sodium will not be able to keep up and the inside of the cell will become more negative ◦as a result of positive ions leaving, the membrane potential will get more negative from -70mV. ◦a change in membrane potential (-70mV) to something more negative is called hyperpolarization of the membrane potential - EX: -70 to -75 is a hyperpolarization -if you have a neuron at -70mV with a K+ leak channel and a gated sodium channel if you open the gate, sodium will flow into the neuron the membrane potential for Na+ is +61.5 going to move the membrane potential inside the cell to something more positive a change in resting membrane potential from -70mV to something more positive (toward the ENa+) is called depolarization of the membrane potential. Depolarization of membrane potential can be -70 to -69. doesn't have to become positive -the force that is acting on these ions to move across the membrane is greater for Na+ than K+ the EP for Na+ is greater due to the Vm being farther away from the equilibrium potential of -70  if you open a channel it is going to pour in potassium has a closer equilibrium potential is the driving force is not as strong to enter the cell