BE 6003 Fall 2010 Neurons !John A. WhiteDept. of Bioengineering[email protected]BE 6003 Fall 2010 What makes neurons different from 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 plasticityBE 6003 Fall 2010 The father of modern neuroscienceRamon y Cajal 1852-1934 Nobel prize 1906 Neuron doctrine: neurons are the basic structural and functional unit of the nervous system http://nobelprize.org Morphological polarityBE 6003 Fall 2010 Morphological polarityRamon y Cajal 1852-1934 Law of dynamic polarization: nerve cells are polarized, receiving information on their cell bodies and dendrites, and conducting information to distant locations through axons http://nobelprize.org Berne and Levy Morphological polarityBE 6003 Fall 2010 Cajal’s arthttp://nobelprize.org Cerebellum Optic tectum Cerebral cortex Morphological polarityBE 6003 Fall 2010 Microtubule-based transportTransport systems Salinas et al. (2008) Curr Opin Cell Bio 20: 445-453BE 6003 Fall 2010 Neuronal action potentials are Na+ and K+ dominatedShape and function of APs Berne and LevyBE 6003 Fall 2010 Refractory periods are shortShape and function of APs White (2000) Encyclopedia of the Human BrainBE 6003 Fall 2010 Crucial features of the neuronal action potentialNa+ channel activation Na+ channel inactivation K+ channel activation Na+ channels are inactivated Impossible to generate another AP Na+ channels still recovering from inactivation K+ channels still recovering from activation Possible, but more difficult, to generate AP White (2000) Encyclopedia of the Human Brain Shape and function of APsBE 6003 Fall 2010 Neurons can fire at high ratesNeuronal firing patterns White (2000) Encyclopedia of the Human BrainBE 6003 Fall 2010 Neurons can fire at high ratesColburn et al. (2003) J Assoc Res Otol 4: 294-311 Neuronal firing patternsBE 6003 Fall 2010 Spike-rate adaptation is very common in neuronsDayan and Abbott, Fig. 5.6 Neuronal firing patternsBE 6003 Fall 2010 SK-type Ca2+-activated K+ channels often play a role in adaptationCalmodulin-binding domain Stocker (2004) Nature Reviews Neuroscience 5: 758-770 Neuronal firing patternsBE 6003 Fall 2010 Cumulative inactivation of Na+ channels is a 2nd mechanism of adaptationFernandez and White (2010) Journal of Neuroscience 5: 758-770BE 6003 Fall 2010 Cumulative Na+-channel inactivation is relieved by fluctuating inputsFernandez and White (2010) Journal of Neuroscience 5: 758-770BE 6003 Fall 2010 Neuronal calcium channelsKhosravani and Zamponi (2006) Physiol Rev 86: 941-966 L: Slow, largely non-inactivating. Found in cell bodies, dendrites. P/Q, N: Slowly inactivating, presynaptic terminals R: More rapid inactivation than P/Q, N. Presynaptic terminals, proximal and distal dendrites. T: Low-threshold, rapidly inactivating. Soma and (distal?) dendrites. Neuronal firing patternsBE 6003 Fall 2010 Multi-state activity in thalamocortical neuronsMcCormick and Pape (1990) J Physiol 431: 291-318. Neuronal firing patternsBE 6003 Fall 2010 Major roles of Ca2+ in neuronsDifferent roles of Ca2+ • Triggers spike-rate adaptation• Involved in bursting • Triggers exocytosis at chemical synapses• Involved in dendritic processing• Local signal for synaptic plasticity• Control signal for cellular homeostasisBE 6003 Fall 2010 Propagation in unmyelinated axonsMethods of propagation White (2000) Encyclopedia of the Human BrainBE 6003 Fall 2010 Myelination of axonsMethods of propagation http://en.wikipedia.org/wiki/MyelinBE 6003 Fall 2010 Myelination of axonsMethods of propagation Berne and LevyBE 6003 Fall 2010 Propagation in myelinated axonsMethods of propagation Na+Na+K+Refractory Spiking ChargingBE 6003 Fall 2010 Myelinated axons have higher conduction velocitiesMethods of propagation http://www.physiol.usyd.edu.au/daved/teaching/cv.htmlBE 6003 Fall 2010 Electrical synapsesMechanisms of synaptic transmission Berne and LevyBE 6003 Fall 2010 Electrical synapses are resistive and bidirectionalMechanisms of synaptic transmission synaptic inputVm(1)+-+-C1G1Vrest1G1Vrest2Vm(2)+-+-C1GgapBE 6003 Fall 2010 Chemical synapsesMechanisms of synaptic transmission Berne and LevyBE 6003 Fall 2010 Chemical synapsesBerne and Levy Ca2+ • Immediately releasable pool: vesicles held close to plasma membrane by SNAREs • Depolarization of presynaptic terminal • Ca2+ entry • Fusion • Diffusion of neurotransmitter across cleft • Binding to postsynaptic receptor • Recycling of neurotransmitter Mechanisms of synaptic transmissionBE 6003 Fall 2010 Resupplying the immediately releasable poolBerne and Levy Ca2+ • Depol. of presyn. terminal • Ca2+ entry • Activation of CaMKII • Phosphorylation of synapsin I • Synapsin I frees vesicles • SNAPs and SNAREs dock the vesicle Mechanisms of synaptic transmissionBE 6003 Fall 2010 Distinguishing features of chemical synapsesGmVrest+-+-Vm+-CmGsynEsynoutsideinsidesynaptic inputUnidirectional Induce post- synaptic conductance change (usually an increase) Mechanisms of synaptic transmissionBE 6003 Fall 2010 Two distinct classes of chemical synaptic 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-messenger systems (usually G-protein-based) – Slow, long-lasting, enormous gainBE 6003 Fall 2010 Major neurotransmitters and neuromodulatorsMechanisms 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 2010 Spontaneous release of single vesicles (quanta)Berne and Levy Mechanisms of synaptic
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