Week's Notes: October 19-23
Week's Notes: October 19-23 NSCI 3310
Popular in Cellular Neuroscience
Joseph Merritt Ramsey
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Popular in Neuroscience
This 12 page Class Notes was uploaded by Joseph Merritt Ramsey on Thursday October 29, 2015. The Class Notes belongs to NSCI 3310 at Tulane University taught by Jeffery Tasker in Fall 2015. Since its upload, it has received 36 views. For similar materials see Cellular Neuroscience in Neuroscience at Tulane University.
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Date Created: 10/29/15
October 19 2015 Synaptic Transmission The Postsynaptic Perspective Continued 0 Shunting Inhibition o This is an additional type of inhibition 0 Consider the scenario I GABA activation opens Chloride Channel so they are open to ow I But if the cell is at 70mV which is fairly common no ow will occur because there is no driving force 0 Potentials are equal I But if Chloride channels are open and an excitatory potential passively diffused down the axon some positive charge is lost because of the channels 0 The open channels respond to the potential change slight depolarization gives Chlorine a positive Driving Force current 0 So some positive charge is lost 0 This is known as Shunting 0 Figure A o This process is described and explained through Ohm s Law I Ohm s law can be used to make sense of the situation I Opening Chloride channels decreases the resistance of the cell 0 Decreased resistance results in decreased Potential 0 V IR Synaptic Modulation 0 Introduction to Modulation o Metabatropic Receptors I Modulation involves slower acting receptors and actions I They don t form ion channels I Respond through signaling cascade 0 Associated with GProtein I Trimer Protein I GProteins bind a Guanosine Nucleotide GDP and GTP o The Receptor is a 7Transmembrane Protein 0 Secondary Messengers I Activates another intercellular ligand 0 Often acts on an ion channel I Often activates a kinase which activates the target protein 0 GProteins o 3 Protein Subunits 39 a y B I These subunits for a membrane associated protein 0 Ligand Binding to the GPCR GProteins Coupled Receptor I The binding to the receptor activates the GProtein 0 Associated to the receptor I a Subunit associates with Guanosine Nucleotide 0 Has GDP and binds GTP instead for activation 0 Initiates the cascade for the Second Messenger 0 Alpha and GTP affect the Primary Effector I By Subunit now separated from the Alpha 0 It can act directly on its target protein 0 Associated with a Transducer I All the action is associated with a specific GProtein known as a Transducer 0 Figure B o GPCR Process I 1 First Messenger Neurotransmitter Binds to receptor I 2 GProtein Activated through GTP Protein is the Transducer I 3 Primary Effector Enzyme Activated Membrane Associated results in production of 2nd Messenger 4 2nd Messenger Formed works on secondary effector 5 Secondary Effector Activated many times a kinase I 6 Phosphorylation of target proteins 0 Types of Metabatropic Interactions o 1 cAMP Messenger System I Overview I Two Subtypes o I B Adrenal Receptor Gs meaning Stimulatory 0 11 a2 Adrenal Receptor G1 meaning Inhibitory o 2 Phosphoinostosol System I Known as the GQ Protein I PLC Targeted Primary Effector I PIPz is an associated protein that forms the 2nd Messenger 0 l DAG o Acts on PKC Protein Kinase C 0 Calcium sensitive mechanism 0 II 1P3 o Acts on Calcium Channels in Smooth ER increasing intercellular Calcium Concentration o 3 Direct By Action I The a unit functions above for 2nd Messenger Cascades o By works directly on channels and proteins 0 Work on GIRK Channels Potassium K Channels I How do they function 0 They create an inhibitory effect 0 1 Opening Potassium Channels 80 Eion o 11 They decrease membrane resistance 0 They act slowly and have a lingering effect I Two Examples 0 I Muscarinic Receptors in the Heart 0 II GABAB receptors in the CNS 0 Metabatropic Receptors Effects on the Cell 0 They can open OR close channels 0 Example on Potassium Channels 0 The Two Main Effects I 1 I 2 o PhysiologicalConsideration o Neurotransmitters Paired With Receptors October 21 2015 Synaptic Modulation 0 Overview of Modulation o Presynaptic occurs before the action potential fires so on the terminal geographically after the Hillock I Diffuse Spillover from the cleft Extrasynaptic I Immediate Retrograde Messenger I Axoaxonic Synapses o Postsynaptic occurs after the signal has reached the cell so geographically before the Hillock I AxodendtriticAxosomatic I Spilled over diffusion can occur here as well but more likely in the Presynaptic Mechanisms because Postsynaptically must occur far up the axon and to soma and dendrites o This method must overcome reuptake and Glial contributions I Glia can produce Gliotransmitters that affect the extrasynaptic membrane on the Soma and Dendrites thus serving as a Post Synaptic modulation mechanism 0 Mechanism Effects I 1 Changes Membrane Potential because of Ion Shifting I 2 Changes Membrane Resistance because of Channel Openings 0 Postsynaptic Modulations Mechanisms 0 Overview I We ve studies and reviewed at Neuropeptide acting as AcH acting on Muscarinic Metabotropic proteins in the heart contrasting the AcH fast acting Ionotropic I Here is a CNS view looking at Metabotropic EPSP s and IPSP s o Excitatory Action I 1 Peptide Example 0 Occurring in the muscular junction I 2 Glutamate o Occurring in the CNS 0 Closes K Channels through GPCR o Closes 0 K causing an overall depolarizing e ect o Increases membrane resistance enhancing charge di usion o Acts mainly on voltage gated channels but affects Leak channels as well 0 Just as in the Peptide Muscarinic Receptor in the muscular Iunction Glutamate Metabotropic receptors cause an elongated effect in the cell 0 Inhibitory Action I 1 GABAB o GABAB is the Metabotropic Receptor 0 It also couples with KChannels 0 Unlike Glutamate Metabotropic receptors GABA opens GIRK channels on the membrane 0 Opening does the opposite of Glutamate I Decreases resistance so shunting occurs I Opens ow of K which hyperpolarizes the cell 0 Also has an elongated effect 0 Presynaptic Modulation Mechanisms 0 Overview I Axoaxonic terminal and Retrograde actions both affect the output of Neurotransmitter in the synapse o Excitatory Action I There isn t one Axoaxonic or Retrograde mGluR is always Inhibitory o Inhibitory Action I 1 Glutamate o Glutamate Metabotropic receptors affects synaptic proteins in the synapse region 0 Protein machinery on the terminal I Synatix I SNAP25 0 Those effects inhibit the budding and excretion of Neurotransmitter vesicles Glutamate and GABA I 2 GABA o GABAB Metabotropic affects Calcium channels thus decreasing Calcium presence in the Presynaptic Terminal 0 The inhibition of Voltage Gated Calcium channels decreases Ca2 presence thus inhibiting Neurotransmitter Vesicle release GABA and Glutamate o Synaptic Recordings of Synaptic Modulation o 1 Glutamate Done through mGluR Metabotropic Glutamate I First measured spontaneous Excitatory Events Glutamatergic EPSP s o A known probability is calculated 0 Small quick Negative Charges I Then measured the cell with mGluAgonist so ligand that activates the Metabotropic Glutamate proteins o The resulting action probability is then observed ad calculated I The mGluR activation in the CNS on an Axoaxonic synapse was found to decrease Excitatory Minis 0 So there was a decrease in vesicular release 0 So we know that mGluR Receptors are Inhibitory on Axo axonic Synapses 0 Not directly inhibitory but inhibitory by increasing the amount of Glutamatergic Ionotropic interactions I How does this occur Biologically o 1 Glutamate spilling over in the form of negative feedback 0 2 Other cells in the region are excreting Glutamate which d uses o 3 New evidence might suggest a dendritic role 0 2 GABA Done through Norepinephrine I First measured spontaneous hyperpolarizing Inhibitory Events GABAB IPSP s 0 These are all inhibitory even the Ionotropic unlike the above Glutamate example 0 Small quick positive charges I Norepinephrine acts as an agonist for GABAB 0 New probability recorded with higher GABAB activation I Found that Norepinephrine causes an increase in events higher probability of GABAA inhibition GABA minis 0 So it facilitates Ionotropic GABA action October 23 2015 Neurotransmitters 0 Defining a Neurotransmitter o 1 Synthesized Stored in the Presynaptic Terminal I This is determined through Immunohistochemistry marking through an antigen to determine location of molecules 0 2 Released with Stimulation I Microdialysis to take up and peform chemical assay 0 3 Specific Receptors Exist on the Membrane for the Transmitter I Neuropharmacology I Autoradiology chemical tag placed on a transmitter to see the receptor 0 General Overview of Neurotransmitters 0 Classes I 1 Small Molecule Amino Acids AcH Biogenics 0 Amino acids have Glycine GABA Glutamate 0 They can be excitatory or inhibitory o Glycine on spinal cord and retina o AcH o Catecholamines o The Tyrosine chain Neurotransmitters o Serotonin I 2 Neuropeptides 0 Always use GPCR o Often Neurohumeral Junction 0 Affects endocrine system I Directly into blood stream I Neuro hormone I Hypothalamic e ects I 3 Unconventional gases Endocannabinoids o Immunohistochemistry I Very important technique used for tracking location movement of particles I An antibody is generated for a particular compound I Generated through Polyclonal Process 0 Foreign compound is given to animal 0 The animals produce natural antibodies which are garnered for use 0 The antibody can then be tagged with the desired amount of additional proteins to increase specificity 0 Discovery of Neurotransmitters I Theory had existed for years before The Reticulate Theory 0 Proposed by Golgi that the nervous system was just a continuous electrical connection I Ramon y Cajal found through Golgi staining that gaps existed 0 So he knew it was not continuous as Golgi suggested 0 So inferred the Neuron Doctrine 0 Chemical synapses exist for communication I 1921 Otto Loewi Experiment 0 A frog heart could be used and stimulated after death and removal 0 Focused on the Vegas Nerve 0 Has an autonomic effect that decreases the heart beat when activated 0 One heart in one chamber had the nerve the other didn t o The two chambers were connected so particles and chemicals could diffuse but there was no electrical connection 0 When the Vegas nerve in chamber I was activated the heart in chamber 11 was activated soon after 0 Determined that the nerve release a chemical thus allowing diffusion to affect the heart 0 Eventually found to be AcH in heart 0 Important Protein Considerations I 1 Cytosolic o Synthesized by free ribosomes synthesize and affect o 2 Types Cytoskeleton and Enzymes o Neuro Application 0 Cytoskeleton transports building blocks and vesicles of Neurotransmitters o Enzymes piece them together I 2 Nuclear I 3 Membrane Associated o 3 Types Attached ER and Vesicular o Neuro Application 0 Neurotransmitters are contained in vesicles 0 Glass Overview 0 1 Small Neurotransmitters I A Amino Acids GABA Glutamate Glycine I B Acetylcholine I C Biogenic Amines o I Catecholamines Tyrosine Derivatives 0 II Serotonin o 2 Neuropeptides o 3 Unconventional Neurotransmitters I A Gases I B Endocannabinoids o Neurotransmitter Creation and Packaging Synthesis and Packaging 0 1 Small Molecule I Cytosolic Proteins and precursor components combine through enzymes to form the Neurotransmitter o This occurs in the Synapse I The Components are sent down the axon unassembled 0 Through slow axoplasmic transport Diffusion through Proteins I After the enzymes put together the transmitter in the Synapse the membrane proteins recognize the Transmitter and form the vesicles 0 II Neuropeptides I Precursor proteins are cleaved into multiple proteins 0 This occurs in the Soma o This cleavage process creates the Neurotransmitter I The packaged vesicles are sent down the Axon 0 Done through Fast Anterograde Transport Through the cytoskeletal proteins 0 Neurotransmitter Action at the Synapse 0 Small Molecule I High concentration on the Presynaptic region especially close to the membrane concentrated at membrane I Clathrin coating surrounds the newly formed Neurotransmitter molecules Dynamin clips to create vesicle before the Neurotransmitters are unpackaged 0 These vesicles are moved by vesicular transport proteins I Recycling Occurs o Reuptake and Packaging taken right back in through Neurotransmitter channels on the presynaptic membrane 0 Uptake Into the Glial Cells glial cells take and break down into basic components 0 Breakdown occurs in both I Vesicles appear as clear smaller dots o Neuropeptide I Already packaged when arriving have higher concentration farther towards the axon than the synaptic membrane 0 So their release occurs farther up as well outside the active site 0 Results in Extrasynaptic Communication Called Volume Transmission because it increases the Extracellular Volume of Neurotransmitter I Vesicles appear as larger black dots o CoRelease I They actually don t act completely separately and are Colocally Stored 0 Small Molecule smaller clear 0 Neuropeptides larger darker I Storage Pool Readily Releasable Pool 0 Predominantly Small Molecule Synaptic Vesicles 0 Needs large action to release Neuropeptides Synaptic Granules I So common small activity mostly affects Small Molecule 0 Large responses affect Neuropeptides as well which are released off the synaptic membrane farther up I Modulation 0 Because of the fast response of Small Molecule they can be depleted from the terminal 0 But Peptides are longer lasting molecules that occur father away from the synapse o This gives Neuropeptides the ability to prime a cellular region because there signal lingers o SmallMolecule Neurotransmitters o 1 Amino Acids I 1 Glutamate Glycine sometimes used as excitatory in Spinal Cord and Retina 0 Overview 0 Amino acid neurotransmitters are used and recycled through terminals 0 Synthesis 0 Glutamine is catalyzed and synthesized by Glutaminase 0 Release 0 Ionotropic Receptors NMDA AMPA Kainate o Metabotropic Receptors mGluR1 to mGlu8 0 Termination of Action Recycling 0 A Astrocytes and neurons have Glutamate receptors on their membranes that take up Glutamate I The molecule is then broken down and Glutamine done by glutamine synthetase precursor is funneled back into presynaptic terminal 0 B Glutamate is also taken up by the presynaptic terminal I But as this point it is merely repackaged not broken down 0 C Glutamate is also not broken down in the cleft contrasting AcH which is broken down by the basements membrane I 2 GABA 0 Synthesis 0 Glutamate is the GABA precursor Gamma Amino butyric Acid 0 Glutamic Acid Decarboxylase and Pyridoxal Phosphate 0 Release 0 Ionotropic Receptors GABAA CI Channel 0 Metabotropic Receptors GABAB A ects K and Ca Channels 0 Termination of Action Recycling 0 A Astrocytes take up but don t break down and reship to terminal like Glutamate o B GABA Transporters present on the axon terminal also take up GABA o 2 Acetylcholine I Action Process 0 Synthesis 0 Acetyl CoA Choline worked on by Acetyl transferase 0 Release and Receptors o Ionotropic Nicotinic o MetabotropicMuscarinic o TerminationRecycling BreakdownUptake o Acetylcholinesterase breaks down into its components in the basement membrane of the Neuromuscular junction 0 Choline is then taken up through its transporter on the terminal membrane I It is then reformed inside the cell I Systems o I Cholinergic System 0 Diffuse System I It occurs everywhere in the brain intrinsic localized creation and CNS effect I Interneurons are present throughout CNS 0 Amygdala is GABAergic extrinsic allowing for body coordination 0 Sources in the Brain I 1 PMT Complex PontoMesencephaloTegmental Complex 0 Basal forebrain connections I 2 Medial Septum o Cortical and Hippocampal projections o Involved in memory and attention 0 Innervates directly on Hippocampus o AcH Fibers are lost early on in Alzheimer s disease I 3 Basal Nucleus of Meynart o Cortical projections 0 Systems overview I The centers are in the brain but lead to projections all throughout the brain I Discrete projections have specific target sites
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