Neuro 1 Exam 1 Study Guide
Neuro 1 Exam 1 Study Guide NEUR 0010
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This 33 page Study Guide was uploaded by Eileen artigas on Saturday October 1, 2016. The Study Guide belongs to NEUR 0010 at Brown University taught by Michael Paradiso in Fall 2016. Since its upload, it has received 89 views. For similar materials see Intro to Neuroscience in Neuroscience at Brown University.
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Date Created: 10/01/16
Lessons Covered In Exam: 1. Neurons and Glia 2. Resting Membrane Potential 3. Action Potential 4. Synaptic Transmission: Physiology and Chemistry 5. Organization of the Vertebrate Brain Neurons and Glia Over 150 types of cells in nervous system - Neurons - Glia Anatomy of a nerve cell Neurons are polarized Parts of neuron- Dendrites, soma, axons, synapse 1 Cell body- Soma, region where general cell functions take place 2 Dendrites- (extending from soma) neurons receive connections from other neurons 3 Axon- long tubular structure, information, electrical activity propagated form one region of nerve cell to more distant regions, axon covered by thick insulating sheath known as myelin (Multiple sclerosis affects myelin structure) 4 Synapse- axons give rise to terminal branches called synapses, information transfer occurs btwn one neuron and another Electrical and Chemical Communication Electrical- using action potential Chemical- around synapse Presynaptic/ Postsynaptic (relative, complex circuit) Post synaptic neuron gets activated as a result of a release of a transmitter substance from presynaptic neuron Most drugs interact with nervous system in chemical synapse Dendrites Most synapses end on dendrites Special receptors in cell membrane bind a neurotransmitter Synapse Full of specialized structures called synaptic vesicles Neurotransmitter substance packaged in the vesicle Space btwn presynaptic and postsynaptic is called the synaptic cleft Synaptic cleft space- a tightly regulated space whose geometry is governed by a complex infrastructure of adhesion molecules. Dendritic Spines Most excitatory synapses end on dendritic spines Shape and density of spine determines strength of neural interactions Spines change with brain development and learning (anatomy not just dry fixed things) Spine abnormalities and intellectual impairment Extent of spine abnormality correlates with extent of intellectual impairment Fragile X syndrome- most common hereditary form of autism Key Functions of Organelles in Soma 2 key functions 1 Protein synthesis- central dogma of molecular biology (start with DNA (in nucleus within the soma) construct messenger RNA (transcription) mRNA translate it into a protein- uses ribosmoes, rough ER, golgi apparatus 2 Energy- ATP (currency for energy) Krebs Cycle in mitochondria produces adenosine triphosphate or ATP, conversion to ADP releases energy Neuro Cytoskeleton Scaffolding proteins affect neuron shape and function Microfilaments, neuro-filaments, microtubules Microtubules Associated Proteins (MAPs) Regulate the assembly and function of the microtubules E.g. tau protein links microtubules Alzheimer’s Disease Cognitive decline and loss of memory due to neural degeneration in the central nervous system What’s going on? Macro brain- cells die, sulci expand, etc. Microscopic Level Tangled plagues Amyloid ubiquitous in the body, normal Beta amyloid or BA is abnormal- sticky, toxic to neurons- amyloid plaques, neurofibrillary tangles Alzheimer's Disease Progression (B amyloid hypothesis) Beta amyloid clumps into plaques Triggers formation of tangles Beta amyloid changes the shape of Tau (hyperphosphoralates tau) As a function of change, tau can't hold together microtubules, start coming away from each other Neuron dies, can't survive without microtubules Leftover tau- tangle ("neuron gravestone") Distorted tau "infects" other neurons (mad cow disease) Prion disease- misfolded protein interacts with proteins in other healthy cells and distort them too Axons- like dendrites, unique to neurons No ribosomes, no protein synthesis (maybe a little) Most protein synthesis occurs in soma Axoplasmic Transport Most proteins are synthesized in the cell body and shipped down the axon Axon hillock (beginning of axon) Axon terminal (end) Anterograde- toward the terminal- kinesin proteins (motor proteins) Retrograde- away from terminal Disease and axoplasmic transport Cold sores- HSV1 (herpes- infection from saliva, enters through broken skin in a nerve terminal, retrograde to soma, replicates so it can spread, something like stress can posit anterograde back to axon terminal and skin due to stress Rabies- animal bite, saliva, infection, retrograde to soma, replication, cell death, virus infects neighboring cells, death in days to weeks Glia Comes from word glue, it was thought they only hold neurons in place 50-100 billion, electrically insulate cells, protect, nourish Astrocytes -most common glia, Do fill spaces between neurons Also involved in regulating concentrations or environment around neurons Guide neurons in development Protect neurons by taking up toxins Oligodendroglia and Schwann Cells Electrically insulate cell with myelin Increase speed of conduction of electrical conduction down axons Oligo (CNS)- myelinate multiple axons Schwann (PNS)- myelinate one axon Node of Ranvier (no myelination) Membrane potential- the electrical potential difference between the inside and the outside of the cell caused by the relative concentrations of charged ions like potassium and sodium inside and outside of the cell and by channels which allow flow of these ions down their concentration gradient The Neuronal Membrane at Rest - Even when a cell is at rest, it is not electrically neutral - Potential energy- stored energy - Difference between inside and outside of membrane at rest - At rest- no action potential - Lots of channels to allow ion transport - At rest, negative (-) inside; positive (+) outside - Difference of charge at membrane, not entire cell - Polar covalent bonds in water make ions dissolve, giving charge - Phospholipid membrane – Hydrophobic tails, hydrophilic head Potential difference in electrical circuits (voltage= potential difference) Potential difference= energy to push electricity through wire, energy to drive ions across cell membrane Ion- molecules with electrical charge Membrane potential- about 65 mV- inside of neuron is 65 mV than outside Resting potential key points Vm= membrane voltage or membrane potential At rest, Vm= -65 mV Vm determined by distribution of ions inside and outside Ion concentrations in axoplasm and extracellular fluid Axoplasm, extracellular fluid Axoplasm (mM) Extracellular Fluid (mM) Potassium 100 5 Sodium 15 150 Chloride 13 150 Calcium 0.002 2 Concentration gradient- concentration changes across the membrane The process of diffusion causes particles to move from regions of high concentration, to regions of low concentration Concentration gradients established by ion pumps Ions pumped or pushed against concentration gradients Sodium-potassium pump Active transport against gradient (ATP changes shape of pump to allow function) (uses an enormous amount of energy, over 50% of all of ATP) 3 sodiums out - 2 potassiums in Pump binds ATP and this changes the shape of the pump protein -pushing them against concentration gradient -membranes regulate flow of ions cell membranes block flow of ions Specialized proteins form ion channels that selectively allow ions to cross Ion channels can be open or closed Ion movement governed by 2 forces 1. Diffusion- process by which particles spread out or mix Diffusion causes particles to move from regions of high concentration to lower (driving them down a concentration gradient) - sodium and potassium always trying to independently balance each other out between the two groups 2. Electrical forces- particles can have a charge- positive or negative (basis of all electricity opposites attract, likes repel) Also trying to balance out charges on both sides Push from diffusion gets balanced by repulsion from the like charge The equilibrium potential occurs when the electrostatic forces caused by having a charge imbalance exactly balance out the force of diffusion that drives those same ions from where they existed in high concentration to where they exist in low concentration- Equilibrium when diffusion force pushing one way equals electrical force pushing the other way Equilibrium Potential and Ionic Driving Force Equilibrium for each ion= Eion - When electrical and diffusional forces are equal in opposite directions Vm- potential difference across the membrane (-65 mV at rest) Ionic driving forceVm- Eion - when membrane sitting on equiibrium potential of that ion, driving force is zero, when out of balance lots of driving force Key Points about Equilibrium 1 Charge difference is right at the membrane- small imbalance accumulates very close to the membrane, generates an electric field across membrane which results in electrical potential 2 Vm Membrane potential that you get is determined by a very large number of ions, but small percentage of ions Equilibrium Potentials for Different Ions Ion E ionequilibrium potential for different ions) K+ -80mV Na+ +62mV Cl- -65mV Ca++ +123mV At rest, membrane is mainly permeable to K+ So Vm is nearEk 1 At resV m= -65mV 2 Na+ much more outside huge driving force pushing inward Ena= +62 mV Drving force= -65 - 62 = -127 -127 mV 1 K+ Ex= -80mV Driving force= -65-(-80)=15 Walther Nernst The Nernst Equation 1920 Nobel Prize (work at age 25) At body temp of 37 degrees c Eion= 61.5/z log [ion] out/[ion]in If concentration inside is greater than concentration of ion out (less than one total), then the log will be less than zero If ion concentration in equals out, log =0 If conc in less than out log greater than 0 Ion Concentrations and driving forces If membrane is only permeable to Na+, then Vm will move towards Ena (+62mV) If only permeable to potassium Vm moves towards Ek (-80mV) Meaning of Driving Force, conductance, current Ionic driving force= Vm- Eion Energy that is pushing an ion in and out, doesn't mean an ion will move, because it needs a channel open and force to push it Ionic conductance= gion Ability of ion to cross membrane Ionic current= conductance times driving force gion (vm-Eion) net movement of ion across membrane Depolarization An increase in Vm Hyperpolarization Decrease in Vm Action potentials- what are they? Rapid increase, then decrease in Vm Action potential = spike, nerve impulse Spike initiation zone= axon hillock Phases of the Action Potential Resting membrane potential Rising phase Peak/overshoot Falling phase Undershoot Action Potential Threshold When a certain potential (threshold) is reached, nerve signal initiates action potential An action potential is initiated when Vm> -40mV "threshold" How reach threshold 1 Sensory input e.g. eat salty chip, step on a tack, hear a loud sound 2 Neurotrasmitter, you get a signal coming from another neuron Refractory Periods Absolute refractory period, short period of time after action potential starts where its impossible for the cell to fire another action potential within about 1msec of previous action potential (While those channels are stuck in the inactive state, we're can't initiate another action potential) Relative Refractory Period- longer period of time in which greater depolarization is needed to get a second action potential (the voltage-gated sodium channels are active again, but the voltage gated potassium channels are still open.) Three Ion Channels involved in action potentials Action potentials require voltage gated ion channels 1 K+ channels not voltage gated 2 K+ channels voltage gated….. 3 Na+ Voltage gated Na+ channels- - able to open and close very quickly - are more likely to be open when the membrane potential is more positive - usually closed when cell is at resting potential voltage gated Na+ channels- voltage alters shape of protein Channels open when Vm> -40mV Positive feedback loo- the membrane potential which used to be at -65 mV, is positive, reversing polarity, the “ball and chain” mechanism inactivates the open channel, stops influx of sodium into cell, it takes potassium channels a bit of time to open in response to more positive membrane potential, but when they do, membrane potential comes back down and even undershoots for a bit Ball and Chain model of Na+ channels Protein plug that can block ion flow Pore can be blocked two ways 1 Channel closed 2 Channel open but plugged Three States of the voltage gated Na+ channel 1 Closed state (de-inactivated) 2 Open state (activated) 3 Inactivated-(open but plugged) Voltage gated K+ channel Voltage gated- open or closed Opening takes 1 milisecond after threshold is reached "delayed rectifier"- brings membrane potential down with a delay The Action Potential Action potential- the signal that conveys information over distances in the nervous system. At rest, the cytosol in the neuron is negatively charged with respect to the extracellular fluid. The action potential reverses this situation so the inside of the membrane becomes positively charged with respect to the outside. Facts: Action potentials Do not diminish as they are conducted along the axon Their frequency and pattern constitute the code used by neurons to transfer information The firing frequency of action potentials reflects the magnitude of the depolarizing current The part of the neuron where an axon originates from the soma, the axon hillock, is also called the spike-initiation zone Phases of the Action Potential- takes 2 miliseconds 1. Resting otential- Potassium channels are open 2. Rising phase- rapid depolarization of the membrane (until Vm reaches a peak value of about 40 mV) (sodium ions rush across the membrane into the cell) 3. Overshoot- inside of neuron is positively charged with respect to the outside 4. Falling phase- rapid repolarization of the membrane (voltage gated sodium channels inactivated , voltage gated potassium channels open, there is a great driving force on K+ ions when the membrane is strongly depolarized, K+ rushes out) 5. Undershoot- membrane is actually more negative than the resting potential 6. Gradual return to Resting Potential The movement of ions through channels that are gated by changes in the membrane potential are crucial to the action potential Threshold- level of depolarization that must be crossed in order to trigger an action potential, enough voltage gated sodium channels open so that the relative ionic permeability of the membrane favors sodium over potassium Refractory Periods Absolute Refractory Period- once an action potential is initiated, it is impossible to initiate another for about one 1msec Relative Refractory Period- relatively difficult to fire another action potential for several milliseconds after the end of the absolute refractory period, higher current required to depolarize neuron to action potential K+ (potassium) o Concentrated twentyfold inside the cell o Membrane potassium current will flow only as long as Vm does not equal Ek (driving force = Vm-Ek) o Voltage- Gated Potassium Channels- do not open immediately upon depolarization delayed rectifier (because potassium conductance serves to rectify and reset the membrane potential) Na+ (sodium) o Concentrated tenfold outside the cell o Sodium gates are “activated”- opened- by depolarizing above threshold and “inactivated”- closed and locked when the membrane potential acquires a positive membrane potential o Sodium Channel structure- when the membrane is depolarized to threshold, the molecule twists into a configuration that allows the passage of Na+ through the pore o TTX- blocks all sodium dependent action potentials and is fatal if ingested. Sodium-Potassium Pump - Works all the time t transport Na+ back across membrane Factors Influencing Conduction Velocity Action potential conduction velocity increases with increasing axonal diameter Smaller axons require greater depolarization to reach potential threshold Myelin - increases action potential conductance - Consists of many layers of membrane provided by glial support cells- Schwann cells in the peripheral nervous system - Does not extend continuously along entire length of axon - Breaks in myelin sheath are nodes of Ranvier - Voltage-gated sodium channels are concentrated in the membrane of the nodes - In myelinated axons, action potentials skip from node to node saltatory conduction Thumbtack Man (seems important) - Step on thumb tack - Skin breaks- sensory nerve endings of the foot - Special ion channels that are sensitive to the stretching of the membrane open and allow positively charged sodium ions to enter the nerve endings - Influx of positive charge depolarizes the membrane of the spike initiation zone to threshold - The action potential is generated - Positive charge that enters during the rising phase of the action potentials spreads down the axon and depolarizes the membrane ahead to threshold - The action potential is continuously regenerated as it sweeps like a wave up the sensory atom - Information is distributed and integrated by other neurons in the central nervous system - Transfer of information from one neuron to another is called synaptic transmission Synaptic Transmission - the process of information transfer at a synapse Synapse- the specialized junction where one part of a neuron contacts and communicates with another The term synapse was coined by electro physiologist Sherrington from Greek synapto- to clasp What do different types of synapses look like? Electrical synapse- direct transfer of ionic current from one cell to the next, - occur at specialized gap junctions - narrow gap is spanned by clusters of special proteins called connexons - - connexons span from one cell to another- ions and small molecules pass through pore - the channel allows ions to pass directly from the cytoplasm of one cell to the cytoplasm of the other - bidirectional - electrically coupled - because most electrical synapses are bidirectional, when the second neuron generates an action potential, it will In turn produce a PSP (postsynaptic potential) in the first neuron - found where normal function requires high synchronicity - most common during early embryonic stage, smooth and muscle cells, liver cells, glandular cells - usually used by glial cells, not so much by neurons Chemical synapse- (Bernard Katz experiment) o the info in the presynaptic cell is passed to the post-synaptic cell by virtue of a chemical signal o Term synapse coined by Sherrington , from greek synapto “to clasp” o Comprise the majority of synapses in the brain o Synaptic cleft separates presynaptic and post synaptic membranes o The presynaptic side of the synapse is usually an axon terminal and contains dozens of small membrane-enclosed spheres called synaptic vesicles o Synaptic vesicles store neurotransmitters o Many axon terminals also contain larger vesicles called secretory granules Synaptic Arrangements If post synaptic membrane is on a dendrite, btwn axon and dendrite, the synapse is axodendritic If post synaptic membrane is on cell body, btwn axon and cell body,the synapse is said to be axosomatic Synapses forming on axon- axoaxonic Neuromuscular Junction- Motor neuron making synapse on skeletal muscle Specialized type of synapse where a nerve cell makes a synapse onto a muscle cell (instead of previous examples where nerve cells synapse with other nerve cells) Muscle- excitable tissue Synaptic junctions exist outside of the synapse Chemical synapses also occur between the axons of motor neurons of the spinal cord and skeletal muscle (neuromuscular junction) Synaptic density- made up of proteins and carbohydrates, keep synapse in place Parts of a Chemical Synapse - Mitochondria- providing energy for terminal bouton - Synaptic vesicles- membrane-bound bubbles, contain the chemicals signal (NT) that will be release by action potential - Gap (20-50 nm) - Synaptic Density- Proteins and carbohydrates that hold the whole thing together, keep synapse in place What happens at synapse? A Form of Signal Conversion. From Pre-Synaptic Cell- 1. an electrical signal (action potential) travels down the axon 2. arrives at terminal bouton? 3. And that electrical signal is turned into chemical signal (neurotransmitter) To Post-Synaptic Cell- 1. Chemical signal travels to post synaptic cell and converted back to electrical signal in the form of a depolarization or hyperpolarization Four stages of synaptic transmission 1. Synthesis and packaging of NT (or chemical signal) 2. Release of neurotransmitter from presynaptic cell 3. Action on the post-synaptic cell (how does chemical singal get converted into hyperpolarization, depolarization) 4. Termination of the signal NT Fall Into Various Classes - Amino acids (have amine group and carboxylic acid group) o Glutamate o Glycine o GABA (gamma- aminobutyric acid) - Monoamines o Seratonin o Acetylcholine - Catecholamines (have catechol group) o Dopamine (DA) o Norepinephrine (NE) o Epinephrine (Adrenaline) - Peptides (made up of strings of amino acids) o Synthesis and Packaging of Neurotransmitter For most NT, everything needed to synthesize and package NTis found in terminal bouton (except peptide NT) Synthesized in the terminal bouton Packaged in tiny membrane-bound vesicles (can be clear or dense-core vesicles, depending on what type of NT is packaged within them) What are the criteria for classification as a neurotransmitter? Many substances have been proposed to be NT but don’t satisfy all criteria. 1. Synthesized by some biochemical process and stored in vesicles in presynaptic cell 2. Electrical stimulation of a cell causes release 3. Elicits an effect on neuron (depolarization, hyperpolarization of a cell) 4. Method of termination (removal of NT) How are neurotransmitters made/ synthesized? Amino acids are the basis of most NT (either amino acids or derivative of amino acids or peptides- strings of amino acids) Synthesized in various levels of complexity Enzymes (proteins that catalyze chemical reactions) in terminal boutton Examples a. Precursor into a product- Glutamate (itself a NT) can be converted to GABA by enzyme glutamic acid decarboxylase b. One enzyme acting on two products to make a single NT- Enzyme choline acetyltransferase (ChAT) takes Acetyl CoA and Cholineto make NT Acetylcholine c. Multi-enzymatic processes- more than one enzyme is involved (tryptophan acted on by tryptophan hydroxylase (enzyme) to make 5- HTP (not NT) then 5-HTP decarboxylase removes a carboxyl group and you form serotonin d. Catacholamine Pathway (4 enzymes involved) - start with tyrosine, tyrosine hydroxylase, dopa, dopa decarboxylase, dopamine, dopamine betahydraxylase, norepinephrine, (PNMT), epinephrine Packing of Neurotransmitters -NT’s synthesized in cytosol, but have to be packaged into vesicles for storage where they sit until AP causes them to be released - often some type of energy requiring process (proton gradient- transporter- drives NT into vesicle) because concentrating NT in vesicle against concentration gradient use transporter to drive concentration of NT into the vesicle Dale’s principle - States one neuron one neurotransmitter - Any given neuron will make one neurotransmitter - Not always true (look above at Catacholmine Pathway, along pathway, three NT’s used (dopamine, norepinephrine, epinephrine, process stops depending on genetic program of the cell) Neurotransmitter synthesis is tightly regulated -You don’t want to make excessive amounts of a neurotransmitter that you don’t need, but just the right amount needed handy How does it happen? Process called End Production Inhibition/ Feedback Inhibition End Product Inhibition/ Feedback Inhibition Think of NT synthesis as assembly line Specifically, think of Catacholamine Pathway Each of these enzymes is a person working to assemble the product for which they are responsible for. The rate at which you make the end product is dependent on the slowest person on the assembly line, that person is the rate limiting person. Control how much and how fast product is made by controlling the action of the rate-limiting enzyme. Most often, the rate-limiting enzyme is the first enzyme in pathway. When enough of a NT is made, it feeds back into the rate limiting enzyme and you stop making that NT. Inhibition is set or relieved depending on current concentration and demand. Peptide neurotransmitter synthesis is a little different - In most cases, everything you need to make a NT is found in the terminal bouton (enzymes, precursors) - Peptide NT- strings of amino acids, composed of various sequences of 20 amino acids used to made proteins in our bodies Where does synthesis of protein start? In nucleus DNA (sequence of string of amino acid coded in genome) RNA (transcribed to messenger RNA, translated into a protein by ribosomes) Protein Chemical structure of peptide- two amino acids, join carboxyl group and amino group to make a peptide bond How does peptide NT end up in a synaptic vesicle in terminal bouton? - DNA in nucleus - Messenger RNA sent out into cytoplasm - Grabbed onto by ribosomes (attached to rough ER) - Protein is now in loomin of ER - Protein buds off into Golgi apparatus (where large pieces are chopped up into smaller active pieces NT) - Packaged into secretory granule - Transported down axon by axoplasmic flow - Matures into synaptic vesicle in terminal bouton Neurotransmitter release - Otto Loewi- won nobel prize for demonstrating conclusively that chemical neurotransmission existed o Experiment o Took two frog hearts (which beat spontaneously if you take the out of the animal and keep it oxygenated, special conditions, etc. o There’s a nerve that goes into the frog heart called the vagus nerve o If you stimulate this nerve, the beating rate would slow down o Set up two frog hearts, connected them to a solution called ringers (buffer solution containing everything cells need to survive) connected the two hearts through a tube which had a valve, o Beat rate of each heart could be measured o Heart one is beating spontaneously o Stimulate vagus nerve with valve closed o Heart 1 slows, heart 2 keeps beating along o Repeats experiment with valve open (liquid can flow from heart one to heart two) o Stimulate vagus nerve o Heart number 2 beats and minutes later also slows o Concluded something was being released from vagus nerve in heart 1 into heart 2, having same effect on heart 2, (would HAVE TO BE some sort of chemical substance) o Named the substance “Vagus Stuff”, later found to be acetylcholine, part of sympathetic nervous system, what controls your heart rate o Later found “Accelerance Stuff”, later found to be epinephrine o Proved chemical neurotransmission exists Neurotransmitter release (cont.) - Triggered by the arrival of the action potential in the axon terminal bouton, depolarization causes voltage-gated calcium channels in the active zones to open - Vesicles fuse with membrane and release their content by a process called exocytosis - The membrane of the synaptic vesicle fuses to the presynaptic membrane at the active zone, allowing the contents to spill out into the synaptic cleft - The vesicle membrane is recovered by the process of endocytosis - SNARE proteins - SNARE proteins involved in the process of release - V-snares- found on vesicle - T-snares- (target snares) found on inner leaflet of synaptic bouton membrane - Synaptotagmin- calcium-sensing protein, binds calcium - When AP arrives at terminal bouton, there are voltage-gated calcium channels in the membrane of terminal bouton, - The voltage-gated calcium channels pop open in response to the AP arriving - Calcium conc. outside of cell much larger than in, rushes into cell down concentration gradient - Calcium then binds to synaptotagmin, causes a huge change in the conformation of the shape of the protein complex such that the vesicle then slams down onto membrane of terminal bouton and fuses with it - Thin of SNARE as spring, when calcium binds, it causes vesicle to be brought down, fusion, NT released - Process completely dependent on calcium entering - Once vesicles fuse, they pinch off and float away and recycle to be loaded again, you want that to happen or the terminal bouton would keep growing and growing Peptide neurotransmitter release is a little different - In this case, the calcium channels are farther away from where vesicles are anchored - More calcium needed to cause vesicles to fuse, more AP stimulation (than monoamine or catecholamine) Action on Post-Synaptic Cell Receptor molecules express on surface of post-synaptic cell Each NT has its own receptor molecule, great deal of specificity built into receptor molecule Receptors recognize very specifically their NT (lock and key fit) complementary protein structure in receptor Receptor recognizes 3D shape of NT Receptors itself have 3D shapes (we know thanks to structural biologists) Neuropharmacology o Inhibitors – prevent normal function of proteins in synaptic transmission o Receptor-antagonists bind to receptors, blocking contact o Receptor-agonists mimic function of NTs SYNAPSES PART TWO Interaction with post synaptic cell will alter the post synaptic cell’s membrane potential How fast does it happen? In which direction does it happen? Both depend on the type of receptor and the type of ion permeability that is going to end up being changed. How rapidly membrane potential changes in post synaptic cell 3 time frames: 1. Fast- milliseconds 2. Intermediate- seconds 3. Slow- seconds to minutes What direction? Depends on the ion whose permeability is changed For example: Change Na+ permeability- depolarizes Change K+ permeability- hyperpolarize Change Cl- permeability- hyperpolarize Change Ca++ permeability- depolarizes When receptors are stimulated, a molecular pathway which ultimately results in the change in permeability of one or more ions Receptors - Fastest mechanism- Ligand (or neurotransmitter) gated ion channel o Trans-membrane proteins, made up of multiple subunits o From top, donut shape, hole in middle (ion channel), the neurotransmitter will bind in the synaptic cleft portion and changes confirmation of the protein complex to make the hole open and allow one of the ions its selective to flow down concentration gradient Conversion of chemical signal back to electrical signal by causing passing of ios Ligand-gated ion channel receptors Acetylcholine will usually gate Na+ Glutamate will usually gate Na+ or Ca2+ GABA will gate Cl- (hyperpolarization) Glycine will gate Cl- (hyperpolarization) Many of these Ligand/NT gated ion channels have subtypes - Glutamate has- AMPA, NMDA, Kainate (have slightly different properties) - depending on where the receptor is and what role its playing you get the various effects that are mediated through glutamate - G-protein coupled receptor (GPCR's) (metabatropic) o All single plpeptide chain, no subunits (unlike 5 protein subunits in ligand gated receptors) o Transmembrane helixes go through membrane 7 times, form bundle o NT binds extracellularly o Very large family of receptors How do these receptors work? Why are they called G- protein coupled receptors? o Despite large variety of NT and hormones that act through these receptors, they all function in much the same way, involves the G- protein o G-protein made of alpha, beta, gamma subunit o Mark Rodbell, Alfred Gilman- shared Nobel prize in physiology and medicine for figuring out how G-coupled protein receptors work (1995) o Guanine-Nucleotide (G in G-coupled receptors) 2 Guanine-Nucleotides involved (play critical role in function of how chemical signal gets transmitted when it binds to a receptor) Guanosine triphosphate- GTP Guanosine diphosphate- GDP o o When there’s no NT in cleft, all parts floating in membrane of post synaptic cell, do not associate o Alpha subunit attached to GDP and beta-gamma subunit o When NT is released into the cleft, it binds to receptor and changes the shape or confirmation of receptor, alpha-beta-gamma subunits bind to it o That attachment event causes GTP/GDP exchange o GTP/GDP exchange reaction- GDP pops off, GTP comes on to alpha subunit, causes conformational change, alpha separates from beta- gamma subunits o Each subunit floats away and affects activity where it bumps into (effector protein) o Alpha-subunit has built within it GTPase- converts GTP back to GDP by removing one of the phosphate groups o GDP ends up bound to alpha subunit and inactivates it o Inactivated alpha subunit, cycles back to the top, re-associates with beta-gamma, turns off activation o As long as there is NT in cleft the cycle will keep running - Two things can happen that alter the activity of post-synaptic cell once you activate the g-coupled protein receptor o G-protein can have direct effects on a signaling partner Direct G- Protein Signaling Muscarinic acetylcholine receptor, binds to receptor, GTP/GDP exchange reaction…. BUT in this case beta gamma subunit floats off and interacts/opens channel (takes seconds) o Or can act through an enzyme which makes other chemical messages and carries signal into the cell further: Intermediating Second Messengers-in this case alpha subunits interacts with enzyme, enzyme produces intermediate chemical second messengers, those second messengers have downstream effects (ultimately result in change in membrane potential) (i.e. Adenylyl cyclase) What's protein kinase? - Group of enzymes, alter the function of proteins - Activity of proteins is determined by conformation/ shape - Protein kinase takes ATP, removes the terminal phosphate from ATP and places it on protein, changing the activity of protein (might activate it, inhibit it, open it or close it if it’s a channel) - Process is called phosphorylation - *Protein phosphatase reverses this reaction - EPSP- excitatory-post synaptic potential - Opening a channel for sodium or calcium channel- depolarization IPSP- inhibitory- post synaptic potential - Opening a channel for chloride or potassium channel- hyperpolarization Receptors produce small EPSP or IPSP, not AP, just small depolarizations, hyperpolarizations Neuron collects all this input in dendritic tree and send message to spike initiation zone If depolarization at spike initiation zone goes from resting potential to around -40mv, you will fire AP in cell. Synaptic integration Mini’s and Quantal Release We think of synaptic transmission as being quantal, each packet is able to depolarize the post synaptic membrane by some fixed amount (about 0.5 mM) quantal release Mini's- miniature post-synaptic potentials, can add up and there's a summation of depolarization NMJ- if your motor neuron fires, you want your muscle to twitch, so quantal release at NMJ is very high, you almost always get enough of a depolarization to cause a muscle to twitch How does this integration occur? Spatial Summation- Synapses in close proximity to each other Temporal Summation- A single synapse with multiple trains of AP’s arriving one after another, release of more NT PROBLEM- Current easily leaks out of membrane because of the properties of the membrane Length constant Position on the membrane where depolarization is 37% of where it is at origin, initiating point (less depolarization can be measured further away from injection point because some of it has leaked out) Lambda- measure of how far the depolarization will spread If a cell has a way to increase the length constant- it will Increase probability that those small depolarizations will reach hillock with enough value to cause an action potential SOLUTION- Excitable dendrite Voltage gated sodium channels dispersed on membrane cause more depolarization- greater spread, small depolarization is enough to open one voltage gated sodium channel, causing more depolarization to reach over to next channel Excitable dendrite (vs. passive which doesn't have sodium channels)- one way of increasing length constant Another way of increasing length constant- cell can use G-coupled protein receptors What about IPSP? Hyperpolarizing Involved in controlling the excitability of the post synaptic cell- If excitatory synapse fires and inhibitory synapse fires, depolarization travels and then canceled out by inhibitory synapse and depolarization never reaches axon hillock Termination of Signaling Stop sending action potentials down terminal bouton Removal of NT- to stop activating receptors -diffusion- what’s been placed in synapse diffuses away (not very efficient but does allow for NT to be removed from cleft (used by peptide NT most) -degradation- chemically degrade so its no longer active (more effective0 enzyme sitting right next to receptor -reuptake -take NT backup into terminal buoton directly, transporters suck NT back up and remove them from cleft, packaged into vesicles Terminating events in postsynaptic cell - Just removing NT from cleft not enough to shut everything down, we’ve activated many intracellular processes (i.e. with g-protein coupled receptors) - G- protein coupled receptors- we’ve made second messengers; enzymes can break down the second messengers (cyclic AMP phosphosterase turns cyclic amp into 5’ AMP which cannot activate alpha subunit anymore) - Calcium- was also released by protein kinase process- How to get rid of it? ATPase in ER drives calcium back into ER, reduces calcium concentration on cytosol - Phosphorylated proteins- get rid of them, protein phosphatase come in and remove phosphate groups from proteins to original state of activity Gross anatomy- what can you see with the naked eye? Is there anything you can tell about that person just by looking at the brain? - in general, no, you can’t even tell if brain is from male or female Different brains from different organisms- differences in size, amount of cortex similarities (all from vertebrates), wrinkly cortex, little structures tucked inside, general organization (cortex, brain stem, cerebellum), speaks to development and evolution Neuroanatomy Planes of section Slices - sagittal- separates left from right (midline, lateral) -horizontal (take a little off the top) -coronal-separates front from back -axial- perpendicular to neuraxis Mid sagittal section- most common Anterior/posterior Rostral/caudal- nose to tail Dorsal/ventral- back to stomach Medial/Lateral- relative something closer to midline, more medial than lateral Ipsilateral/ Contralateral- relative (decussation- crossing the midline) In a rat, rostral and caudal, anterior posterior, one in the same In bipedals, anterior and rostral same at tip of brain but as you come down to spinal cord, shift 90 degrees Cortex- outside surface of cerebral hemispheres Brain stem- sitting right on top of spinal cord Structure on top of spinal cord- cerebellum Brain Lobes: Occipital lobe - located under occipital bones visual Temporal Lobe- located under temporal bones auditory Parietal Lobe- located under parietal bones somatosensory Frontal Lobe- located under frontal bone motor output Spinal Cord and Peripheral Nervous System Spinal Cord - Dorsal root ganglia- bulb (cell bodies in dorsal ganglia, cluster of cell bodies) - Dorsal- sensory in - Ventral- motor out Peripheral Nervous System o Somatic – voluntary control Motor neurons from ventral spinal cord Cell bodies in CNS; axons in PNS Dorsal root ganglia – clusters of cell bodies of somatic sensory neurons Input – afferent Output – efferent o Autonomic – visceral/involuntary Sympathetic – arousal Parasympathetic – calming White- white matter- mostly axons (cables) Grey- grey matter- mostly neurons cell bodies Muscle- moves or contracts Gland- secretes Central Nervous System: • cerebrum (cerebral hemispheres divided by sagittal fissure; right hemisphere controls left side of body, vice versa) • cerebellum (as many neurons as the cerebrum; movement control center; extensive connections with cerebrum and spinal cord; left side of cerebellum controls left side of body, right controls right) • brain stem (relays information from spinal cord to cerebrum and cerebellum; regulates vital functions; most primitive part of brain, most vital to life) • spinal cord (encased in vertebrate column; communicates with body via spinal nerves, which attach to cord via dorsal root or ventral root) o dorsal root (sensory information) o ventral root (motor information) Peripheral Nervous System: • somatic PNS (all spinal nerves that innervate skin, joints, muscles under voluntary control) • visceral PNS (aka autonomic nervous system; neurons that innervate internal organs, blood vessels, glands The Meninges: - Bag surrounding the brain - Function: structural support of the brain - The fluid that inflates the “bag”- cerebrospinal fluid - covers the brain and spinal cord • dura mater the outermost layer, “tough mother,” tough inelastic bag • arachnoid membrane appearance and consistency of spider web – sub arachnoid space- cerebral fluid circulates in sub arachnoid space Subdural space- vacuum-sealed space • pia mater “gentle mother,” follows surface of brain all the way around, thin membrane covering the brain in intimate contact with it; separated from arachnoid by fluid filled space Blood/Brain Barrier- all capillaries of brain closely monitored, etc. Ventricular system (filled with Cerebrospinal fluid) o Lateral ventricles start in medial forebrain and wrap posteriorly and then anteriorly in the temporal lobes o Third ventricle Shaped like a donut due to thalamus connecting between hemispheres o Cerebral aqueduct – thin channel in midbrain o Fourth ventricle – last ventricle of the brain in the hindbrain, draining into spine o Cerebrospinal fluid produced by choroid plexus in ventricles Absorbed into blood at arachnoid villi Development Nervous system- a human embryo has a three-ring structure: ectoderm on the outside, mesoderm in the middle, and endoderm on the inside. nervous system- derived from a small stretch of cells within the dorsal ectoderm called the neural plate. Neural plate – rapidly expanding flat plate; folds together inward (groove) Forms neural tube, which becomes the CNS Neural plate begins infolding- neurulation o End product of primary neurolation- brain and majority of the spinal cord Neural Tube Prosencephalon- most rostral; becomes forebrain Mesencephalon – becomes midbrain Rhombencephalon – most caudal; becomes hindbrain o open anterior and posterior segments of the neural tube are called the anterior and posterior neuropores. o Bidirectional tube closure occurs in zipper-like fashion, anteriorly and posteriorly, rather than in a single direction. o Failure of neural tube closure can affect the entire neural tube or be limited to one of the neuropores. o If the anterior neuropore does not close, anencephaly results, which means that cranial structures, such as the brain, do not form—an obviously neurologically devastating result. o Failure of posterior neuropore closure results in spinal canal defects collectively called myeloschisis, which are subcategorized into different forms of spina bifida. Spinal Cord o Cervical – close to neck o Thoracic – upper torso o Lumbar – lower back
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