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U of U BIOEN 6003 - Neurons

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1BE 6003 Fall 2008NeuronsJohn A. WhiteDept. of [email protected] 6003 Fall 2008What makes neurons differentfrom cardiomyocytes?• Morphological polarity• Transport systems• Shape and function of action potentials• Neuronal firing patterns• Different roles of Ca2+• Methods of propagation• Mechanisms of synaptic transmission• Mechanisms of intracellular integration• Glial support systems• Synaptic plasticity• Homeostatic plasticity2BE 6003 Fall 2008The father of modernneuroscienceRamon y Cajal1852-1934Nobel prize 1906Neuron doctrine: neurons are the basicstructural and functional unit of the nervoussystemhttp://nobelprize.orgMorphological polarityBE 6003 Fall 2008Morphological polarityRamon y Cajal1852-1934Law of dynamic polarization: nerve cellsare polarized, receiving information on theircell bodies and dendrites, and conductinginformation to distant locations through axonshttp://nobelprize.orgBerne and LevyMorphological polarity3BE 6003 Fall 2008Cajal’s arthttp://nobelprize.orgCerebellumOptic tectumCerebral cortexMorphological polarityBE 6003 Fall 2008Microtubule-based transportTransport systemsSalinas et al. (2008) Curr Opin Cell Bio 20: 445-4534BE 6003 Fall 2008Neuronal action potentials areNa+ and K+ dominatedShape and function of APsBerne and LevyBE 6003 Fall 2008Refractory periods are shortShape and function of APsWhite (2000) Encyclopedia of the Human Brain5BE 6003 Fall 2008Crucial features of the neuronalaction potentialNa+ channel activationNa+ channel inactivationK+ channel activationNa+ channels are inactivated Impossible to generate another APNa+ channels still recovering from inactivationK+ channels still recovering from activationPossible, but more difficult, to generate APWhite (2000) Encyclopedia of the Human BrainShape and function of APsBE 6003 Fall 2008Neurons can fire at high ratesNeuronal firing patternsWhite (2000) Encyclopedia of the Human Brain6BE 6003 Fall 2008Neurons can fire at high ratesColburn et al. (2003) J Assoc Res Otol 4: 294-311 Neuronal firing patternsBE 6003 Fall 2008Spike-rate adaptation is verycommon in neuronsDayan and Abbott, Fig. 5.6Neuronal firing patterns7BE 6003 Fall 2008SK-type Ca2+-activated K+ channelsoften play a role in adaptationCalmodulin-binding domainStocker (2004) Nature Reviews Neuroscience 5: 758-770Neuronal firing patternsBE 6003 Fall 2008Neuronal calcium channelsKhosravani and Zamponi (2006) Physiol Rev 86: 941-966L: Slow, largely non-inactivating. Found incell bodies, dendrites.P/Q, N: Slowlyinactivating,presynaptic terminalsR: More rapidinactivation than P/Q,N. Presynapticterminals, proximaland distal dendrites.T: Low-threshold,rapidly inactivating.Soma and (distal?)dendrites.Neuronal firing patterns8BE 6003 Fall 2008Multi-state activity inthalamocortical neuronsMcCormick and Pape (1990) J Physiol 431: 291-318.Neuronal firing patternsBE 6003 Fall 2008Major roles of Ca2+ in neuronsDifferent roles of Ca2+• Triggers spike-rate adaptation• Involved in bursting• Triggers exocytosis at chemicalsynapses• Involved in dendritic processing• Local signal for synaptic plasticity• Control signal for cellular homeostasis9BE 6003 Fall 2008Propagation in unmyelinatedaxonsMethods of propagationWhite (2000) Encyclopedia of the Human BrainBE 6003 Fall 2008Myelination of axonsMethods of propagation 6003 Fall 2008Myelination of axonsMethods of propagationBerne and LevyBE 6003 Fall 2008Propagation in myelinated axonsMethods of propagationNa+Na+K+Refractory Spiking Charging11BE 6003 Fall 2008Myelinated axons have higherconduction velocitiesMethods of propagation 6003 Fall 2008Electrical synapsesMechanisms of synaptic transmissionBerne and Levy12BE 6003 Fall 2008Electrical synapses are resistiveand bidirectionalMechanisms of synaptic transmissionsynaptic inputVm(1)+-+-C1G1Vrest1G1Vrest2Vm(2)+-+-C1GgapBE 6003 Fall 2008Chemical synapsesMechanisms of synaptic transmissionBerne and Levy13BE 6003 Fall 2008Chemical synapsesBerne and LevyCa2+• Immediately releasable pool:vesicles held close to plasmamembrane by SNAREs• Depolarization of presynapticterminal• Ca2+ entry• Fusion• Diffusion of neurotransmitteracross cleft• Binding to postsynaptic receptor• Recycling of neurotransmitterMechanisms of synaptic transmissionBE 6003 Fall 2008Resupplying the immediatelyreleasable poolBerne and LevyCa2+• Depol. of presyn. terminal• Ca2+ entry• Activation of CaMKII• Phosphorylation of synapsin I• Synapsin I frees vesicles• SNAPs and SNAREs dock thevesicleMechanisms of synaptic transmission14BE 6003 Fall 2008Distinguishing features ofchemical synapsesGmVrest+-+-Vm+-CmGsynEsynoutsideinsidesynaptic inputUnidirectionalInduce post-synapticconductancechange (usuallyan increase)Mechanisms of synaptic transmissionBE 6003 Fall 2008Two distinct classes of chemicalsynaptic receptorsMechanisms of synaptic transmission•Ionotropic– Postsynaptic receptor is an ion channel– Binding of ligand (neurotransmitter) changes Popen– Fast, transient, small gain•Metabotropic– Postsynaptic receptor is tied to postsynaptic 2nd-messengersystems (usually G-protein-based)– Slow, long-lasting, enormous gain15BE 6003 Fall 2008Major neurotransmitters andneuromodulatorsMechanisms of synaptic transmission•Amino acids–Glutamate–GABA (gamma aminobutyric acid)–Glycine•Acetylcholine•Catecholamines–Norepinephrine–Dopamine–Serotonin•Peptides–Opiods (endorphins, enkephalins, dynorphins)–Substance P•Gases–Nitric oxide–COBE 6003 Fall 2008Spontaneous release of singlevesicles (quanta)Berne and LevyMechanisms of synaptic transmission16BE 6003 Fall 2008Ionotropic EPSPs and IPSPsBerne and LevyMechanisms of synaptic transmissionBE 6003 Fall 2008Quantal releaseBerne and LevyMechanisms of synaptic transmission17BE 6003 Fall 2008Binomial modelMechanisms of synaptic transmission! P(q = k) =N!k!(N " k)!pk(1" p)n"kE[q] = Np#2= Np(1" p)BE 6003 Fall 2008Classical model of neuronalintegration of inputsMechanisms of intracellular integrationBerne and LevyExcitatory inputstend to innervatedendritesInhibitory inputstend to innervatecell bodies18BE 6003 Fall 2008Spatial and temporal summationMechanisms of intracellular integrationBerne and LevyBE 6003 Fall 2008Cable theoryMechanisms of intracellular integration! 2#2Vm#x2= m#Vm#t+ Vm(x,t)%Vm0! "=a2#iGm [=] mm$M= Cm/Gm [=] ms19BE 6003 Fall 2008DC response

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