MANY Student questions of the dayMANY Student questions of the day……..Q1: Why do neurons have axons: wouldn’t synapses between lots of small cells be just as good?A1: Chemical synapses are slow, and transmission speedA1: Chemical synapses are slow, and transmission speeddown a neuron would plummet (by orders of magnitude).down a neuron would plummet (by orders of magnitude).Q2: Why not have electrical synapses?A2: These are rapid, but as any electrical synapse A2: These are rapid, but as any electrical synapse would generate an action potential in the postsynaptic neuron, would generate an action potential in the postsynaptic neuron, different inputs cannot be integrated.different inputs cannot be integrated.Q3: Can one neuron get both excitatory and inhibitory inputs?A3: Yes, these generally come from separate synapsesA3: Yes, these generally come from separate synapsesonto the same neuron. The neuron then summates these inputs onto the same neuron. The neuron then summates these inputs to decide whether to generate an action potential.to decide whether to generate an action potential.Q4: Are amphetamines neurotransmitters?A4: No. Amphetamines alter neurotransmitter release/re-uptake.A4: No. Amphetamines alter neurotransmitter release/re-uptake.7.0134.23.07Systems INervous System 3STARTSTARTFOUNDATIONSFOUNDATIONSHow-to 1How-to 1FORMATIONFORMATIONHow-to 2How-to 2SYSTEMSSYSTEMSPROBLEMSPROBLEMSBIOCHEM GENETICS CELL BIO.MOL. BIOSTEM CELLS,CLONINGREC. DNACELL TYPE &POSITION 3DSTRUCTUREGENOMICSVIRUSESCANCERHUMANDISEASELIFELIFENERVOUSSYSTEMIMMUNESYSTEMSBIOLOGYFUTUREFUTUREexcitatory/inhibitorysynapsesexcitatory/inhibitorysynapsessensory neuron interneuron motor neuroninputoutputCIRCUITaction potentialyes or no?action potentialyes or no?action potentialyes or no?H. Sive MIT 2007Action potentials = message Synapses = connections which regulate decision to “fire”Circuits = which neurons connectInput = neuronal, environmental: Output = movement, otherCircuits, synapses and action potentials1CircuitsZebra finch song circuit2Viewing wordsListening to wordsSpeaking words Generating wordsPurves 46.16: multiple brain nuclei (regions) work together = language (PET scan)3Do neurons know where to go?Do neurons know where to (re-)connect?eye rotated 180oNasalTemporal4Sperry’s frog retina rotation experimentExperiment: rotate retina 180o, assay where axons regrow 5H. Sive MIT 2007retinaoptic tectum (brain)T NR Cnormalaxon trajectoriesR CN Tpossible outcome:axons findincorrect targetsConclusion: axons “know” where to growactual outcome:axons find theirnormal targetsR C180o rotated retinaN TMolecules involved in retinal axon migrationNasal retinal axons choose to migrate onrostral and not caudal tectal membranes(stripe assay) rostralrostralrostralrostralcaudalcaudalcaudalTectal membrane6retinaoptic tectumN TR Cnormalaxon trajectoriesExplaining Sperry’s retina rotation experimentactual outcome:axons find theirnormal targetsT N180o rotated retinalow ephrin ligandhigh ephrin ligandlow eph receptorhigh eph receptorR Clow ephrin ligandhigh ephrin ligandlow eph receptorhigh eph receptorConclusion: N/T axons express different Eph receptor levelsand follow an ephrin gradientNot covered in lecture.For your interest only!!!The growth cone7From Molecular Cell Biology/ LodishZone of actin polymerizationFront/leading edgeDirection ofmovementnucleusRear/trailingedgeLamellipodia/filopodiaActin polymerization during cell movementRemember this?! (Formation III)axonmicrotubulesmicrofilaments(F-actin)Filopodium/ lamellipodium(thin) (thicker)GROWTHCONE= Receptorfor short range/long range guidance moleculeH. Sive MIT 20078Axon guidance via long/short range attractive/repulsive signalsBallabore et al, 20059growth coneAxonal growth cone10Collapse of the axonal growth cone due to a repulsive signal11Guidance signalsAxonal outgrowth:choice of laminin versuspolylysine substrate12Axon guidance in thespinal cord: transverse sectionfloor plateroof platetrochlearaxonsgrow away from floor platedorsalventralcommissuralaxons growtowards and turn at floor plateCell bodyGrowth coneH. Sive MIT 200713Spinal cord sectionCommissural axons (green) , cell bodies (red)Cell bodiesCell bodiescell bodiesaxons14zdorsal spinal cordfloorplatecommissuralaxon outgrowthroofplatedorsal spinal cordno outgrowthExplant assay to test floor plate/roof plate activity on commissural axonsH. Sive MIT 200615Conclusion: floor plate attracts commissural axonsExplant assay for axon guidance activityDorsal spinal cordFloor plateDorsal spinal cordTissue culture cellsgrowingaxonsno axonoutgrowth16Netrin1 RNA is expressed in floor plateNetrin1 protein is expressed in a gradientextending from floor plateTessier-Lavigne et al17Wild type Netrin1-/-Loss of function: Netrin is required for normal commissural neuron (red) outgrowth18Netrin receptors promote attraction or repulsionDCC-DCCnetrinattractiveTyrosine kinasesGTPases (Rho)PhosphoinositolCytoskeletal remodeling (F-actin, microtubules)Ca2+influxCAM KinaseGrowth cone extension/turningTyrosine kinasesGrowth cone collapseCytoskeletal remodelingG-actinDCC-UNC5DCC-UNC5repulsivenetrinH. Sive MIT 2007plasmamembrane19Stabilizing connectionsNerve growth factor is a neuronal survival signal (Prof. Rita Levi-Montalcini)- NGF+
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