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Published byJarvis Truran Modified over 9 years ago
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Ligand gated ion channels Channel structure –Heteropentamer –4-transmembrane pass subunits Neurotransmitter diversity Post synaptic potentials –Excitatory –Inhibitory Modulation
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Structure Pentameric Charged pore –Cation/anion selective –4-pass monomer Cytoplasmic basket
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Receptor activation 2-5 ligands per channel Ion selectivity Inactivation
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Neurotransmitters TransmitterInotropic receptor Structure AcetylcholineExcitatory (nicotinic) Na/K channel GlutamateExcitatory Na/Ca/K NMDA/AMPA SerotoninExcitatory Na/K GlycineInhibitory Cl- GABA -Aminobutyric acid Inhibitory Cl- TransmitterMetabotropic receptor AcetylcholineMuscarinic receptor GlutamateMetabotropic glutamate SerotoninSerotonin receptor GABAb-type GABA DopamineDopamine receptor NorepinepherineAdrenergic receptor
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Acetylcholine, serotonin receptors Ach, Nicotinic AChR –K+/Na+ permeable –~30 pS 17e6 Na + /s @ 90mV –Broadly distributed, including striated muscle 5-HT 3, 5-hydroxytryptamine –Na+/K+ –Esp raphne nuclei Attention/cognitive function Depression (SSRIs)
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Glutamate receptors NMDA (N-methyl-D-aspartate) –Na+/K+/Ca2+ –Mg 2+ dependent voltage gating AMPA (amino-3—hydroxy-5-methyl- 4isoxazolepropionic acid) Quisqualate –Modest, 12 pS conductance –Some are Ca2+ permeable; excitotoxicity Kainate –Low, 4 pS conductance
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Inhibitory neurotransmitters Structurally similar to excitatory –5 subunit –Dual-ligand binding Chloride conductance –Adult: inhibitory –Developmental: excitatory Higher intracellular Cl- K+/Cl- co-transporter –Upregulated late in development –Exports Cl- to establish ~-120mV equilibrium potential
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GABA A receptor -Aminobutyric Acid –Cl- channel, 18 pS, 20 ms Major inhibitory receptor in CNS Anesthetic target (barbiturates) –Channel agonists –Increase conductivity Addiction –Reduced expression of calmodulin kinase
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Glycine receptor Relatively little receptor diversity –4 alpha subunits, 1 beta –Strychnine binding –90 pS Retina, spinal motor, spinal pain Phosphorylation reduces conductivity Zinc –nM-uM zinc potentiates –>10 uM Zn2+ inhibits
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Neuronal Anatomy Cell Body/Soma Dendrites –Input-spine Axon –Output-bouton
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Dendrite Morphology Multiple synapses Multiple morphologies Synaptic plasticity EPSP/IPSP VI Popov et al., 2004 Neuroscience
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Endplate potential Miniature endplate potentials –Release of a single NT quantum –Quantal size –Receptor efficacy –NT reuptake/metabolism Voltage at “silent” endplate Spike histogram
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Endplate potential Actual NT release causes EPSP/IPSP –Single synapse –Extremely regular –Sub-threshold Spatial summation –Multiple inputs –High resistance dendrites –No AP means no amplification Axon hillock –High density Na V channels –Origin of AP
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Spatial summation Depolarization due to single channel Multple synchronous channels Na + r r r
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Spatial summation Transmission loss Gulledge, et al 2005
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Temporal summation Facilitation of EPSP by previous EPSP –Depolarization from depolarized state –Modification of channel. Potentiation
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Soma signal processing
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Signal modulation Potentiation Pre-synaptic inhibition Plateau potentials Metabotropic interaction Synaptic remodeling
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NMDA receptor mediated plasticity Glutamineric synapses have both AMPA and NMDA receptors –Long term potentiation: Tetanus increases subsequent EPSPs –Tetanic depolarization relieves Mg 2+ block –Calcium induced channel phosphorylation increases conductance –Long term potentiation Ca2+ influx via NMDA receptors Ca 2+ ->PKA-|I1->PP1-|AMPA Low frequency stimulation Low Calcium I1 activates PP1 Decreases AMPA High frequency stimulation High Calcium I1 is inhibited Reduces PP1 Increases AMPA
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Inhibitory modulation Synaptic fatigue –NT depletion Presynaptic inhibition –Reduces AP initiated current & Ca 2+ influx –Metabotropic block of Ca channels –Activation of Cl- channels
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Plateau potentials Neuronal bistability –Bursting triggered by brief depolarization –Terminated by brief hyperpolarization Mechanism –T-Type calcium channels –Sodium current BurstRest
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Metabotropic neurotransmission G-protein coupled receptors –No direct ionic current –Activation of secondary signaling cascade
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Sea slug (tritonia) locomotion Characteristic escape response Alternate, vigorous body flexion Simple neural circuit Lawrence & Watson 2002
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Tritonia CPG Escape is a programmed response –Katz, et al., 2004 Stimulate sensory neurons to elicit escape Dorsal Swim Interneuron Ventral Swim Interneuron Ventral Flexion Neuron Dorsal Flexion Neuron Flex Extend Intracellular potential of neurons
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Tritonia Metabotropic Neuromodulation DSI stimulation triggers fast and slow depolarization –Slow depolarization is GTP dependent –Blocked by non-hydrolysable GDP- -S Stimulation Recording Slow metabotropic depolarization Fast Ionotropic depolarization Blocks metabotropic process
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Synaptic remodeling Rearrangement of neural networks Hebbian elimination –Vision –Synchronous signals are strengthened Remodeling of dendritic spines –Calcium dependent cell motility Stimulation of cultured neuron results in rapid development of a new dendritic spine Goldin, et al., 2001
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