PHGY 209: Introduction to the Nervous System PDF

PHGY 209 Introduction to the Nervous System David Ragsdale Montreal Neurological Institute ([email protected]) Remember an event from your past Remember an event from your past “… our mind is the pattern of information processing running on a special kind of ma...

PHGY 209 Introduction to the Nervous System David Ragsdale Montreal Neurological Institute ([email protected]) Remember an event from your past Remember an event from your past “… our mind is the pattern of information processing running on a special kind of machine: our brain.... Its information processing all the way down and all the way up.” Read Montague  Organization of the Nervous System Central Nervous System Brain Peripheral Peripheral Nervous System Nervous System Afferent fibers (Sensory neurons) Autonomic fibers Enteric nervous system The nervous system comprises around 100 billion neurons. Santiago Ramon y Cajal Neurons are electrical cells  Neurons talk to each other.  Communication takes place at specialized sites called synapses  The human nervous system contains hundreds of trillions of synapses, creating neural networks of vast complexity. Neurons come in an enormous range of shapes and sizes. Santiago Ramon y Cajal Despite their morphological diversity, neurons share characteristic structures, including the cell body (soma), branching dendrites and a single axon, which may extend anywhere from a few millimeters to more than a meter. Initial Presynaptic segment Dendrites terminals Soma Axon Adapted from Fig. 2-4 in, Kandel, Schwartz and Jessel, Principles of Neuroscience, Vol 4, McGraw-Hill, 2000.  Information Dendrites Axon Soma Axon Axons The electrical properties of neurons The Resting Membrane Potential The inside of a typical neuron is -60 to -70 mV, compared to the outside. This resting membrane potential is caused -70 mV by a small excess of negatively charged ions inside the cell. + - + - - + - + + - - + + - - - - - + - - + - - + + + + - + + - + - - - - - + - + - + - + + + - - - + - - - + - + + - - + + - - - + - + + - + + + + + + + - - - - - + - + - - - + - + - - + - + - + - - + The resting membrane potential is created by concentration gradients for the various physiological ions... Na + K+ Cl- Na+ K + Cl- A- OUTSIDE INSIDE Na+ = 145 mM Na+ = 10 mM K+ = 5 mM K+ = 140 mM Cl- = 100 mM Cl- = 5 mM A- = 50 mM A- = 145 mM … and the selective permeability of the resting membrane to K+ ions. Na + K+ Cl- Na+ K + Cl- A- OUTSIDE INSIDE Na+ = 145 mM Na+ = 10 mM K+ = 5 mM K+ = 150 mM Cl- = 100 mM Cl- = 5 mM A- = 50 mM A- = 155 mM At rest, the neuronal membrane is highly permeable to K+, but much less permeable to the other physiological ions. K+ gradient Na+ A- A- Na+ Na+ K+ A- A- A- Na+ A- K+ Na+ K+ A- Na+ K+ A- Na+ K+ A- A- A- A- A- A- Na+ K+ K+ K+ A- A- Inside membrane Outside K+ ions leak out of the cell, down their concentration gradient, leaving behind impermeant, negatively charged ions. K+ gradient Na+ A- A- Na+ K+ Na+ A- A- A- Na+ A- K+ Na+ K+ A- Na+ A- K+ Na+ K+ A- A- A- A- A- A- K+ Na+ K+ K+ A- A- Inside membrane Outside Accumulation of unpaired negative ions inside the cell creates an electrical gradient that tends to pull K+ ions back into the cell. K+ gradient Electrical gradient A- A- Na+ K+ Na+ A- A- A- Na+ A- K+ Na+ Na+ A- K+ K+ Na+ K+ K+ A- A- A- A- A- K+ K+ A- A- Inside membrane Outside When the chemical and electrical gradients are equal, the system is at equilibrium. The membrane potential at equilibrium is described by the Nernst equation. K+ gradient Electrical gradient A- A- Na+ K+ Na+ A- A- A- Na+ A- K+ Na+ Na+ A- K+ K+ Na+ K+ K+ A- A- A- A- A- K+ K+ A- A- Inside membrane Outside  The Nernst Equation The membrane potential at equilibrium is described by the Nernst equation. 2.3RT [ion]out Eion = zF log [ion]in The equilibrium potential for K+ (EK) is the main factor determining the neuron resting membrane potential. 5 mM 61 EK+ = z log 150 mM = -90 mV  The resting permeability to K+ is caused by leak channels. Leak channels are proteins that form K+ selective pores through the membrane. They are open at the resting membrane potential. K+ A- A- K+ A- Na+ K+ Na+ A- Na+ K+ Na+ A- K+ A- Na+ A- A- K+ K+ K+ Na+ A- A- K+ A- A- A- A- K+ A- Na+ K+ A- Na+ Inside membrane Outside If the membrane of the resting neuron were exclusively permeable to K+, the voltage difference across the membrane would = EK = -90 mV. In fact, it’s closer to -70 mV. 0 mV ERest = -70 mV EK = -90 mV Na+ A- A- Na+ Na+ K+ A- A- A- Na+ A- K+ Na+ K+ A- Na+ K+ A- Na+ K+ A- A- A- A- A- A- Na+ K+ K+ K+ A- A- Inside membrane Outside To understand why, we must consider that each ion has an equilibrium potential, determined by its charge and its internal and external concentrations. The Nernst equation can be used to calculate the equilibrium potentials for each of the physiological ions. Na + K+ Cl- Na+ K + Cl- +70 mV -90 mV -80 mV OUTSIDE INSIDE Na+ = 145 mM Na+ = 10 mM K+ = 5 mM K+ = 150 mM Cl- = 100 mM Cl- = 5 mM A- = 50 mM A- = 155 mM The resting membrane potential is a bit more positive than EK, because there is a small inward leak of Na+, which pushes the membrane slightly toward ENa. ENa = +70 mV 0 mV ERest = -70 mV EK = -90 mV Na+ A- A- Na+ Na+ K+ A- A- A- Na+ A- K+ Na+ K+ A- Na+ K+ A- Na+ K+ A- A- A- A- A- A- Na+ K+ K+ K+ A- A- Inside membrane Outside  Key Points The membrane potential is determined by concentration gradients and relative permeabilities of membrane to different physiological ions. The concentration gradients don’t change much, but the permeabilities can change rapidly and dramatically. The dominant permeability makes greatest contribution to the membrane potential. (At rest, the dominant permeability is to potassium, so the membrane potential is close to EK.)  The Sodium-Potassium Pump The sodium and potassium gradients are maintained by the sodium-potassium pump, which uses the energy produced by ATP hydrolysis to pump sodium out and potassium in against their concentration gradients. K+ K+ Outside ATP ADP Inside Na+Na+Na+ The Action Potential Axons propagate information from one region of the nervous system to another, by brief electrical impulses called action potentials. Action potentials usually start at the initial segment of the axon and then propagate down the length of the axon to the presynaptic terminals. Axon  The action potential is a transient depolarizing spike that moves down the axon. At the action potential peak the membrane potential approaches ENa. Axon Initial Presynaptic segment terminal +30 mV -70 mV Action potential The action potential is initiated when the membrane potential depolarizes to a threshold level. The threshold is determined by the properties of ion channels in the axon membrane, especially a class of channels called voltage- gated sodium channels. Action potential -50 mV (Threshold potential) -70 mV (Resting potential) Voltage-gated sodium channels The rising (depolarizing) phase of the action potential is caused by sodium ions flowing into the cell through voltage-gated sodium channels. Sodium channels have three critical properties: 1) They are closed at the resting membrane potential, but open when the membrane depolarizes. 2) They are selective for Na+. 3) The open channel rapidly inactivates, stopping the flow of Na+ ions. Sodium channel activation and inactivation Closed Open Inactivated Na+  Na+ ENa The Action Potential Membrane potential (mV) +50 10% of sodium channels open The rising phase of the action Na+ current -50 mV 0 potential is a regenerative -50 process. Depolarization of the -70 EK membrane to threshold Initial segment activates a small fraction of Na+ ENa sodium channels, which further Membrane potential (mV) 60% of sodium channels open +50 depolarizes the membrane, Na+ current 0 0 mV resulting in activation of more -50 sodium channels, and so forth. -70 Na+ EK This positive feedback ENa mechanism results very rapidly Membrane potential (mV) +50 100% of sodium channels open in maximal activation of sodium Na+ current 0 +30 mV channels, a large sodium influx, -50 and depolarization of the -70 EK membrane from the resting ENa level to a new level, near ENa. Membrane potential (mV) +50 Sodium channels inactivated Action potential Inactivation terminates the Na+ current -70 mV 0 sodium influx, causing the Na+ current -50 membrane to relax back to its -70 EK original resting level. Time (msec) The density of voltage-gated sodium channels in the axon membrane is much higher than the density of leak potassium channels, so at the peak of the action potential, the Na+ permeability swamps the resting permeability for K+. Axon Na+ channels Leak K+ channels Voltage-gated potassium channels In addition to sodium channel inactivation, a second factor contributing to the falling phase of the action potential is the delayed activation of voltage-gated potassium channels. ENa +50 Membrane potential (mV) Action potential 0 Na+ current Membrane Current -50 EK K+ current Sodium-Potassium Pump (again) The sodium and potassium gradients run down faster when the neuron is firing a lot of action potentials. The pumps have to keep up with neuronal activity. K+ K+ Outside ATP ADP Inside Na+Na+Na+ Action potential propagation is caused by spread of electrotonic currents from the site of the action potential , which excites adjacent regions of axon. Na+ channels Na+ channels Na+ channels Na+ channels Na+ channels Na+ channels inactivated inactivated inactivated inactivated inactivated inactivated Na+ Na+ Na+ Na+ Na+ Na+ Na+ Initial Toward presynaptic segment terminal For a few milliseconds after the action potential, the sodium channels are inactivated and the membrane is completely unexcitable. This period is called the absolute refractory period. Over a somewhat longer period, during which the voltage-gated potassium channels are open, the membrane potential overshoots its resting level. During this relative refractory period, the axon is less excitable and is unlikely to fire an action potential. Absolute Relative ERest = -70 mV EK = -90 mV Each action potential is an all-or-none event. Neurons send information by means of the frequency and pattern of action potentials. Transduction of pressure on skin surface into neuronal activity Skin surface Action potentials  Sodium channels are the molecular targets for naturally occurring neurotoxins Puffer fish make tetrodotoxin, Phyllobates frogs secrete an extremely potent inhibitor of batrachotoxin, a powerful sodium channels. sodium channel activator. http://animals.nationalgeographic.com/animals/ http://animals.nationalgeographic.com/animals/ fish/pufferfish/ amphibians/golden-poison-dart-frog/ Sodium channels are also modulated by pyrethroid insecticides, as well as scorpion and anemonae toxins. Sodium channels are blocked by therapeutically important drugs, including local anesthetics and some antiepileptic agents. Local anesthetics Antiepileptics Lidocaine Phenytoin (Dilantin) Benzocaine Carbamazepine (Tegretol) Tetracaine Cocaine Rapid propagation of action potentials is File:Squidward.png important for survival, especially in situations that require rapid, reflexive responses. In squids, evolution solved the problem of how to send fast-moving signals from one end of the body to the other by making giant axons, 1000 times fatter than our axons. This strategy works because the propagation rate Loligo pealei of the action potential is proportional to axon diameter. Squid axon Mammalian axon Myelination and saltatory conduction Vertebrate neurons solve the problem of how to make a small axon with a high conduction velocity by wrapping the axon in an insulator called myelin. Myelin is formed by Schwann cells (in the PNS) or oligodendrocytes (in the CNS). nodes of Ranvier myelin Myelin wraps around the axon http://en.wikipedia.org/wiki/Myelin Saltatory Conduction (cont.) Myelin acts as an electrical insulator, enabling charge to travel farther and faster down the axon. Myelin is interrupted by periodic gaps called nodes of Ranvier. These regions of bare axon contain very high concentrations of voltage-gated sodium channels, enabling the signal to be regenerated at periodic intervals. Na+ Na+ Na+ influx influx influx Initial segment Myelin Node Multiple sclerosis is caused by loss of myelin. Demyelinated region Multiple sclerosis lesions in the cerebral cortex http://www.sciencephoto.com/media/259687/enlarge  White matter corresponds to regions of the brain and spinal cord that contain mostly myelinated axons. Gray matter comprises cell bodies, dendrites and synapses. White matter Gray matter Synaptic physiology There are three main types of synapses Axodendritic Spine synapse Shaft synapse Axosomatic Axoaxonic Dendrites and spines of a pyramidal cell of the cerebral cortex. Richards et al., Proc Natl Acad Sci U S A. 2005,102:6166-71. A single neuron, through its branching axon may make synapses with many other neurons. Structure of the Synapse “Protoplasmic kisses … the final ecstasy of an epic love story.” Ramón y Cajal Axon Postsynaptic spine Structure of the Synapse Axon Presynaptic terminal Presynaptic vesicles Active zone Synaptic cleft Postsynaptic density Postsynaptic spine Electron micrograph of brain synapses Presynaptic terminal Activation of voltage-gated calcium channels triggers neurotransmitter release. Ligand-gated ion channels are postsynaptic receptors for transmission at brain synapses. Postsynaptic spine  Fundamental steps of chemical synaptic transmission The action potential invades the Synaptic vesicles fuse with the 3. Transmitter diffuses across presynaptic terminal. Calcium presynaptic membrane, the cleft and activates channels open, resulting in Ca2+ releasing transmitter into the receptors in the postsynaptic influx into the terminal synaptic cleft. membrane.  Calcium-dependent fusion of a synaptic vesicle at an active zone. Cytoplasm Ca2+ Synaptic cleft Postsynaptic cell The postysnaptic response to neurotransmitter is either an excitatory postsynaptic potential, (EPSP) which depolarizes the postsynaptic membrane, or an inhibitory postysnaptic potential (IPSP), which hyperpolarizes the postsynaptic membrane. Excitatory synapse -58 mV -60 mV EPSP Inhibitory synapse -60 mV IPSP -65 mV The main excitatory neurotransmitter in the brain is glutamate. Glutamate Excitatory synapse  Rapid excitatory transmission at synapses is primarily due to the actions of glutamate on two types of ionotropic glutamate receptors: 1) AMPA receptors and 2) NMDA receptors. Glutamate Presynaptic terminal Excitatory synapse AMPA receptors NMDA receptors Postsynaptic spine AMPA receptors and NMDA receptors are examples of ionotropic receptors. This means that they are ion channels, that open in response to binding of small molecules (e.g. neurotransmitters) to receptor sites on their external surfaces.  AMPA receptors are responsible for the “fast” EPSP at excitatory synapses. Presynaptic terminal Glu Glu binding site AMPA Receptors AMPA receptors are responsible for the “fast” EPSP at excitatory synapses. Presynaptic terminal Glu AMPA receptors are responsible for the “fast” EPSP at excitatory synapses. Presynaptic terminal + + Na+ + + + + + + + + + + +  The EPSP is a small, transient depolarization of the postsynaptic spine. Presynaptic terminal Excitatory synapse + + -58 mV + + EPSP -60 mV information 20 msec In typical brain synapses, the depolarization caused by a single EPSP is > a few millivolts and last around 20 msec. -58 mV EPSP -60 mV 20 msec The depolarization caused by a single EPSP too small to depolarize the axon initial segment to threshold. Action potential -50 mV threshold -70 mV From 50 to 100 EPSPs must sum at the initial segment to initiate an action potential. These near-simultaneous EPSPs can come from multiple synapses acting in synchrony and/or from individual synapses, activated at high frequencies. Action potential threshold  NMDA Receptors Key Properties – At resting membrane potentials, the pore is blocked by Mg2+; depolarization expels Mg2+, enabling the pore to conduct. – The open pore is highly permeable to Ca2+ as well as monovalent cations. Ca2+ Mg2+ Ca2+ Glutamate glycine Mg2+ -70 mV -50 mV  At -70 mV almost all the synaptic current at an excitatory glutamate synapse is carried by Na+ through AMPA receptors; however, if the postsynaptic membrane is depolarized, a substantial Ca2+ current flows through NMDA receptors. NMDA AMPA Ca2+ Na+ Mg2+ Ca2+ Na+ Glutamate Glutamate Mg2+ -70 mV -50 mV Highly active excitatory synapses become stronger (i.e. the EPSPs become larger). This process, called synaptic plasticity, involves NMDA receptors. Long-term potentiation (LTP) is a Single action potential model of synaptic plasticity. Presynaptic terminal Excitatory synapse Mg2+ + + - 60 mV EPSP Control High frequency activity depolarizes the Burst of action potentials postsynaptic spine, removing Mg2+ block of NMDA receptors and enabling them to conduct Ca2+. Presynaptic terminal Excitatory Mg2+ synapse + Ca2+ + - 60 mV Induction EPSPs are larger, hours after induction Single action potential of LTP. Presynaptic terminal Excitatory synapse Mg2+ + + + + -60 mV EPSP LTP  Summary of LTP + + + + + + Control Induction LTP  High concentrations of glutamate are toxic to neurons. This phenomenon, called excitotoxicity, is thought to involve calcium influx through NMDA receptors. Glu Excitotoxicity is likely to contribute to neuronal degeneration after stroke and in some neurodegenerative diseases.  Inhibitory synapses Excitatory synapse Inhibitory synapse -60 mV IPSP -65 mV The main inhibitory neurotransmitter in the brain is -aminobutyric acid (GABA). The postsynaptic receptor responsible for the IPSP is called the GABAA receptor. GABA GABAA receptors The GABAA receptor is an ionotropic receptor. Activation of the GABAA receptor causes influx of Cl- , which hyperpolarizes the postsynaptic membrane. Cl- -65 mV -70 mV  Synaptic Integration A typical cortical neuron receives thousands of synaptic inputs, some excitatory, others inhibitory. Excitatory inputs tend to be located on dendritic spines, whereas inhibitory inputs are often clustered on or near the cell soma, where their inhibitory effect is maximal. Whether-or-not a neuron fires an action potential at any given moment depends on the relative balance of EPSPs and IPSPs. The output of the neuron, on the other hand, is the all-or-none firing of action potentials down the axon. Glu GABA GABA Glu GABA GABA Glu Glu Glu Metabotropic receptors (G-protein coupled receptors, GPCRs)  Glutamate synapses have both ionotropic receptors (AMPA and NMDA receptors) and metabotropic glutamate receptors (mGluR’s) Presynaptic terminal metabotropic Ionotropic receptors Glutamate receptors (AMPA, NMDA receptors (mGluR’s Activation of mGluR’s by glutamate relays a chemical signal to the inside of the postsynaptic neuron.. Presynaptic terminal Glu Activation of mGluR’s by glutamate generates a chemical signal , called a second messenger, inside the postsynaptic spine. Presynaptic terminal + + + + + + + 2nd messenger + + + + +  2nd messangers activate a range of cellular proteins, including ion channels, protein kinases and transcription factors. Closed ion Activated ion channel channel Nucleus  2nd messangers activate a range of cellular proteins, including ion channels, protein kinases and transcription factors. Closed ion Activated ion channel channel enzyme Activated protein kinase Activated transcription factor Nucleus Neuromodulators Glutamate and GABA activate both ionotropic and metabotropic receptors. (The metabotropic glutamate and GABA receptors are called mGluRs and GABAB receptors, respectively.) Many types of neurotransmitters interact mainly, or entirely with metabotropic receptors. These substances, such as dopamine, serotonin and norepinephrine, as well as neuropeptides such as endorphins, are often referred to as neuromodulators. They are not directly involved in the fast flow of neural information, but modulate global neural states, influencing alertness, attention and mood. Neurons that release neuromodulators often originate in small brainstem or midbrain nuclei. Their axons project diffusely throughout the brain. Dopamine projections in the human brain SN VTA SN – Substantia Nigra VTA – Ventral Tegmental Area Neuromodulator systems are important targets for a wide range drugs. For example, antidepressants, such as Prozac, affect serotonergic transmission, whereas amphetamines, cocaine and other stimulants typically affect dopamine and norepinephrine transmission.