Unformatted text preview: Nerve/synapse: Electrically excitable cells tissues nervous system and muscle Mind and body separates Descartes now, we think they're together Spinal cord continuation of the brain (same type of neurons) o Relay center periphery to brain and brain to periphery CNS brain and spinal cord Peripheral nervous system o afferent fibers coming in (sensory) o efferent fibers going out (motor) to muscles o efferent outputs autonomic fibers for organs homeostasis connected to enteric system peristalsis in organ (gut) linings brain has specific/discrete functional regions Neurons: o Dendrites: antenna; reaching into extracellular space; receives input from other neurons amount of branching determines amount of input o Axon: varying lengths; propagate information from different parts of nervous system electrical signals o Soma: cell body; nucleus, DNA, protein synthesis; part the most like other cells o Initial segment: electrical signals initiated; where soma meets axon o Presynaptic terminal: end of axon o Neuron can have lots of dendrites, but just one axon Neuron's propagate electrical signals o Ohm's Law Electricity Voltage: separate charges, electrical pressure Membrane potential: can then lead to flow across membrane; potential energy difference, difference in charges across membrane Current: flow of electrical charge Resistance: resistance to flow of current Resting membrane potential: o Inside of neuron (-)ive compared to the outside -70mV o Potential energy gradient o Very small imbalance of charge with excess of negative inside o If neuron is sitting around doing nothing, inside is more negative o Uses potential energy to do work starting point for propagating electrical signal o Where does it come from [ ] gradient of K+ when cell at rest [high] inside, [low] outside tends to want to leak out of the cell All physiological ions have [ ] gradients Membrane is impermeable to all except K K+ can pass freely in and out, and this makes the inside (-)ive Pores allow K+ to pass, but none other K+ wants to leak out down gradient As inside of the cell gets more negative, electrical force builds up in the opposite direction (i.e. negative is pulling positive K in) balances equilibrium If we know [K+] inside and out, can find the potential at equilibrium K leaks out until reach equilibrium potential Movement of ions is very small detectable only by electrical gradient ion channels regulate flow of electrical currents Potassium leak channels o Resting o Pore very selective for K+ completely excludes all others o Always open i.e. a hole in the membrane o 1000s on the neuron o Responsible for the resting potential Physiological ions o [Na] high outside ENa+ = +50mV o [Cl] high outside ECl- = -70mV o [K] high inside o Each ion is trying to push the membrane towards its own equilibrium potential Why is resting potential slightly more +ive than K+ equilibrium o Some of the other ions squeeze through and influence potential o Na wants into the cell Na pushes the potential to be more +ive Na permeability is 1/25 resting permeability of K+ therefore doesn't affect potential as much as K+ o Each ion has equilibrium potential, but since K is most permeable pushes the membrane potential the most slight influence from Na+ o Dominant permeability has the greatest influence Ion channel gating o Proteins, pores pathways for ions o Most are selective for certain ion How it regulates flow o Voltage-activated when membrane potential changes Generally when becomes more +ive o Receptors Binds ligand to open channel synapse Na+ - K+ Pump o Pumps ions to create [ ] gradient o Requires ATP hydrolysis o Maintains [ ] gradients, and therefore membrane potential o Pumps Na out of cell against its [ ] gradient o Pumps K into the cell against its [ ] gradient If axon is injected with an electrical signal at one end (i.e. inject + charges) o Charges start to spread out and will fizzle out over short distance if just passively injected needs mechanism for signal propagation o Electrotonic currents flow passively along axon Action potential: neurons need to propagate systems over long distances o Spike in the membrane potential o Actively propagated down the axon o Tiny segment, therefore needs to be propagated down the axon o Begins at initial segment o Propagates down to presynaptic terminal o Membrane goes from resting potential to +30-40mV and drops back down very rapidly spike membrane depolarization (gets more+) Voltage-gated Na channels o Specialized protein allows neurons to propagate signal o Closed at resting o Activate if membrane becomes more positive DEPOLARIZATION o Only open for very short time o All or none phenomenon once it's started, always goes to completion o -50mV depolarized enough to open some of Na channels o More depolarization, more channels open, more Na comes in more Na coming in causes
membrane to depolarize even more o Membrane potential will tend to move towards equilibrium potential of Na (because it is the most permeable through the membrane) peaks at +30mV (which is about the equilibrium of Na) o Takes less than a millisecond o Voltage-gated channels inactivate membrane goes back to resting potential o One way to think + charged Na flows into initial segment o Other way peak of action potential, Na permeability becomes dominant tends towards its equilibrium potential o Threshold the action potential is initiated when the membrane potential depolarizes past a threshold determined by the properties of ion channels in the axon membrane (voltagegated Na channels) Threshold is typically -50mV Depolarization below the threshold won't do anything Once hit threshold, has to go all the way up o Density of voltage-gated channels in the axon membrane is much higher than the density of leak K channels At rest, leak channels dominate, during action potential, Na dominates Leak channels always exist Na during action potential 25x greater than the K permeability Goldman equation Voltage-gated K channels o In the axon o Closed at resting membrane potential and open during depolarization o K channels open slowly delay i.e. don't open until Na channels are inactivating o Creates a second pathway for K to leak out of the axon makes falling phase back to resting membrane potential much faster o Reach their peak during falling phase of action potential Peak of the action potential few excess + charges in the cell slightly positive Na-K pumps constantly maintaining gradients o Concentration of ions doesn't change a lot but electrical changes are detectable Process continuously regenerates itself Inactivation of Na channels go back to being closed when the membrane is back to resting potential takes times Trailing behind the action potential is a segment that is unexcitable (inactivated channels) means that signal cannot go back to the wrong direction o Otherwise there is no directionality in the axon Myelination and saltatory conduction o Neurons have mechanisms for making action potentials rapid Pain sensing neurons encode intensity by varying how fast action potential fires (because can't vary the size of action potentials Nature has evolved neurotoxins that act on ion channels o Because ion channels are so important major targets for toxins o Na channels especially targeted o Tetrodotoxin very specific for Na channels; blocks with very high affinity; blocks action potentials in neurons and muscle cells o Batrachotoxin tree frogs; secrete potent toxin in skin; used by natives to coat arrow tips in South America; specific to sodium toxin; causes channel to be irreversibly open; neuron becomes very depolarized; seizures and convulsions; deadly toxin o Toxins have evolved to act very specifically on Na channels Drugs o Into the nerve and blocks Na channels in axons why numb o 10,000x less potent than tetradotoxin but potent enough to work in local areas o Antiepileptics Suppress and prevent seizures Block voltage-gated Na channels a little bit to prevent excessive activity, but not enough to block all channel activity Speed of action potentials o Axons not necessarily designed to propagate that rapidly o But sometimes need them to go very quickly large diameter proportional to speed of action potential resistance fat axon has low resistance to flow of electrotonic currents fat axon faster, skinny axon slow o Squid escape response; action potential from one end to the other Axon is really big squid giant axon axon 1 mm wide (can actually be dissected) Wouldn't work for humans couldn't fit that many big neurons into body Alternative mechanism myelination Myelination and saltatory conduction o Insulation myelin coats axons made from specialized cells o CNS oligodendrocytes o PNS Schwann cells o Wrap the axon up o Gaps nodes of Ranvier Contains lots of voltage-gated Na channels No Na channels in the myelinated areas o Saltatory conduction: in steps Electrotonic currents can spread farther and faster Signal fizzles out more slowly As getting to point of fizzling out, another node of Ranvier another influx of Na Continues down the length of the axon Opening and inactivation of Na channels occurs only at periodic gaps, and then signal is `coasting' in between the nodes Faster way of propagating signals than having Na channels all the way down the axon because opening of Na channels is the slowest part of the process Boost, coast, boost, coast... o Multiple sclerosis Degradation of myelin Axons don't propagate action potential normally Loss of sensation, movement abnormalities o Which neurons have myelin and which ones don't? Axons that need to send messages over long distances are myelinated Short distances within brain normally not myelinated o Myelin fatty whitish outer part of brain white matter (large collections of myelinated axons) Greyish regions cell bodies and dendrites Synapses o Where neurons communicate with each other o Quadrillion synapses in brain o Number and complexity of interconnections responsible for computational capacity of brain o 3 kinds of synapses Axosomatic Continuations of axodendritic synapses To the cell body Axodendritic what we talk about the most Presynaptic terminal of one neuron synapses with dendrites of another neuron Main form of neuron communication Spine synapse ends of specialized structures (spines) on dendrites where synapse occurs Shaft synapses right onto shaft of dendrite mainly inhibitory synapses More surface area on dendrites why there are more synapses there Axoaxonic Presynaptic terminal with presynaptic terminal o Neurons have elaborately branching dendrites for synapses Single neuron receiving input from 100s or 1000s of other neurons o Structure of synapse Presynaptic and postsynaptic terminals not actually touching gap between them synaptic cleft where neurotransmitters cross Presynaptic vesicles spheres of plasma membrane that contain neurotransmitters Active zone docked vesicles, ready to be released Postsynaptic terminal interacts with neurotransmitter and sends signal Presynaptic coming in Postsynaptic receiving signal Presynaptic terminal voltage-gated Ca channels closed at resting potential, and open during action potential Ca flows into the cell when opened Postsynaptic terminal neurotransmitter receptors ligand-gated ion channels open when they bind on extracellular side to neurotransmitter o Process Action potential propagates down presynaptic axon Depolarization of presynaptic terminal Activation of voltage-gated Ca channels Ca flows in Very sensitive to small changes in [Ca] because inside [ ] is practically zero Ca flow triggers fusing of vesicles with plasma membrane and release neurotransmitter into cleft Neurotransmitter flows across cleft and binds to receptors on postsynaptic terminal opens ion channels changes electrical properties of postsynaptic terminal Ca bind to proteins in the presynaptic terminal which triggers vesicles being released Electrical signal (presynaptic) chemical signal (cleft) electrical signal (postsynaptic) Number of vesicles quite small maybe only 1 per synapse o Vesicles are tethered at the plasma membrane Don't need to know names of proteins o One of the proteins involved in holding the vesicles also Ca o Lots of toxins at act this complex eat up proteins involved in process so that vesicles can't fuse with plasma membrane synapses don't work no more wrinkles (botox) o Excitatory and inhibitory synapses One or the other Excitatory make postsynaptic cell more likely to propagate action potential EPSP excitatory response that occurs in the postsynaptic cell Inhibitory makes postsynaptic cell less likely to propagate action potential IPSP inhibitory response that occurs in postsynaptic cell Glutamate most common neurotransmitter in the brain Presynaptic terminal releases glutamate from their vesicles Amino acid Diffuses across synaptic cleft and interacts with glutamate receptors on postsynaptic membrane o NMDA receptors o Non-NMDA receptors AMPA receptors (kainate) AMPA receptors Responsible for EPSP Ion channel Glutamate binds to receptor site and opens pore of AMPA receptor Permeable to sodium ions flow into the cell that region of dendrite becomes more +ive depolarized small depolarization and short Glutamate released and diffuses and pumped out of synaptic cleft signal gone ensures that EPSP is short can send lots over short time EPSP small, transient depolarization of postsynaptic cell o Signal has to passively travel through cell body towards initial segment gets weaker and weaker o Generally, one EPSP is not big enough to trigger action potential in postsynaptic cell Get a whole bunch of EPSP at the same time each one spreads and converge on initial segment and add up to push past action potential threshold 50-100 EPSPs to get action potential happening at almost the same time NMDA receptors Special role at glutamate synapses Pore is permeable to Ca ions Make synapse stronger with bigger EPSP by being very active and letting in lots of Ca with NMDA receptors how we learn and memory strengthening of synapses plasticity GABA receptors Inhibitory Presynaptic terminal releasing GABA and postsynaptic terminal sensitive to it Neurotransmitter for inhibitory GABA GABA receptors on postsynaptic terminal activated when GABA binds Pores permeable to Cl ions push Cl into the cell makes postsynaptic becomes hyperpolarized more ive also transient IPSP (brief hyperpolarization of postsynaptic membrane) Synaptic integration Exhibitory and inhibitory axons converging on same postsynaptic neuron Postsynaptic neuron being bombarded with both types of signals Depends on proportion of EPSP to IPSP at any given time o Firing pattern depends on dominant input o Adding together all inputs to determine output Metabotropic receptors o Slow response and lasts longer o Mediated by metabotropic receptors o Not ion channels Proteins in plasma membrane with external binding site for neurotransmitter o Causes change in shape of receptor activates receptor o Relays signal to inside of cell intracellular signalling molecule (secondary messengers) can activate ion channels from the inside of the postsynaptic cell takes longer mediate slow EPSP Neuromodulators o Fast signals are the ones carrying information around the body o Slow responses have different role o Metabotropic receptors for glutamate and for GABA o Substances interact only with metabotropic receptors neuromodulators dopamine, serotonin... o Overall brain function and states mood o These kinds of synapses vulnerable Drugs prozac depression gets more serotonin in brain Drugs of abuse have effect by more dopamine in the brain, either directly or indirectly cocaine, alcohol o Learning Objectives: By the end of this section, you should be able to Identify the different structures of the neuron (the dendrites, axon, etc). Explain resting membrane potential. Describe the processes involved in the initiation and propagation of the action potential. Explain what the action potential is for. Understand what myelin is for and how it works. Describe the structure of the synapse. Explain what synapses are for. Explain how neurotransmitter is released from the presynapticterminal and how it affects the postsynaptic membrane. Identify the properties of AMPA receptors, NMDA receptors and ionotropic GABA receptors. Explain the role of NMDA receptors in synaptic plasticity. Understand the difference between fast synaptic transmission, mediated by ionotropicreceptors and slow synaptic transmission, mediated by metabotropicreceptors. Understand how the integration of EPSPsand IPSPsdetermines the firing of action potentials in the postsynaptic neuron. Explain presynapticinhibition and presynapticfacilitation by axoaxonicsynapses. ...
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- Fall '07
- Na channels