Chapter 48 Neurons, Synapses, and Signaling Overview: Lines of Communication o Tropical cone snail Carnivore eats fish Injects

jects venom and paralyzes prey in seconds This venom contains a mixture of molecules that disable neurons Disrupts neuronal control of locomotion and respiration o Neurons: Nerve cells that transfer information within the body Their SPECIALIZED STRUCTURE allows them to use pulses of ELECTRICAL CURRENT to receive, transmit, and regulate the flow of information over long distances within the body o Communication of neurons: Consists of long-distance electrical signals & Short distance chemical signals To transfer information from one cell to another, neurons rely on chemical signals over short distances Neurons transmit SENSORY INFORMATION, CONTROL HEART RATE, COORDINATE HAND AND EYE MOVEMENT, RECORD MEMORIES, GENERATE DREAMS, ETC. All of this is transmitted as an electrical signal o The identity of the information being transmitted is encoded by the connections made by the active neuron o Interpreting signals involves sorting a COMPLEX SET OF NEURONAL PATHS AND CONNECTIONS o In complex animals, the processing is carried out by large groups of neurons organized in BRAINS or GANGLIA 48.1 Neuron organization and structure reflect function in information transfer o Squid: has large nerve cells active predator surveys environment, spots prey

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signals travel from the brain to the muscular mantle along giant AXONS to its mantle causing muscle contractions that propel it forward Axons: nerve cell extensions of large diameter Information processing: Sensory input: (PNS) Integration: (CNS) Neurons that carry out integration are organized in CENTRAL NERVOUS SYSTEMS; include brain and nerve cord Motor output: (PNS) Relies on neurons that extend out of the processing centers and TRIGGER MUSCLE or GLAND ACTIVITY MOTOR NEURONS transmit signals to muscle cells causing them to contract Neurons that carry information in and out are the PERIPHERAL NERVOUS SYSTEM. Bundled together, these form nerves SPECIALIZED POPULATIONS OF NEURONS handle each stage of info processing SENSORY NEURONS transmit information from eyes and other sensors that detect EXTERNAL STIMULI (light, sound, touch, heat, smell, or taste) or INTERNAL CONDITIONS (blood pressure, blood CO2 levels, and muscle tension) This info is sent to processing centers in brain or ganglia Here they are analyzed and interpreted (integration) INTERNEURONS form local circuits of connecting neurons in the brain Neuron structure and function: Neurons organelles are located in the CELL BODY Extensions of the cell body are called DENDRITE: RECEIVE signals from other neurons AXON (1): Extension that TRANSMITS signals to other cells

 Longer than dendrites AXON HILLOCK base of axon where signals are generated Near its far end, the axon divides into many branches: Transmits info at a SYNAPSE (synaptic terminal) Chemical messengers called NEUROTRANSMITTERS pass info to the receiving cell Transmitting neuron PRESYNAPTIC Neuron, muscle, or gland cell that receives signal - POSTSYNAPTIC Depending on the number of synapse, the neurons shape can be very different Axons with multiple branches transmit info to many cells Neurons with many dendrites can receive input through many synapses The neurons require supporting cells called GLIAL CELLS or GLIA. Nourish neurons Insulate axons Regulate extracellular fluid They outnumber neurons in the mammal brain o Concept Check: Sensors in your ear transmit stimuli (sounds) to your brain where they are integrated (recognize your name being called). Signals from your motor neurons cause muscle contractions (neck turning to sound) Increased axon branching would reach more postsynaptic cells, enhancing coordinated responses to signals Communication in neurons involves only some cells in the body, not all (nerve cells); Neurons direct signals from one specific location, to another 48.2 Ion pumps and ion channels establish the resting potential of a neuron

o Ions are UNEQUALLY distributed between the interior of cells and the fluid that surrounds them The INSIDE of a cell is NEGATIVELY charged to the OUTSIDE This is called MEMBRANE POTENTIAL The membrane potential of a RESTING neuron (not sending a signal) is its RESTING POTENTIAL o (-60 - -80mV) o The attraction of opposite charges across the plasma membrane is a source of POTENTIAL ENERGY o Inputs form other neurons or other stimuli cause changes in the MEMBRANE POTENTIAL These acts as signals that transmit and process information Rapid changes in m. potential are what enables us to see a flower, read a book, or climb a tree o Chemical and electrical forces: form, maintain, and alter membrane potentials o Formation of the resting potential: Potassium and sodium ions play an essential role in resting potential. K+ and Na+ have CONCENTRATION GRADIENTS across the plasma membrane Concentration of K+ is highest INSIDE THE CELL Concentration of Na+ is highest OUTSIDE THE CELL The gradients are maintained by a Na+ K+ PUMP Use the energy of ATP hydrolysis to transport Na+ OUT OF THE CELL and K+ INSIDE THE CELL 3 Na+ ions out for every 2 K+ ion in Pumping generates an export of positive charge There is a voltage difference because of ION MOVEMENT through ION CHANNELS Pores formed by clusters of specialized proteins in the membrane Allow ions to DIFUSE BACK AND FORTH carrying with them electrical charge

 Any resulting movement, generates membrane potential The ion channels convert the chemical potential energy to electrical potential energy -> SELECTIVE PERMEABILITY Allow only certain ions to pass Not many Na+ channels = not much Na+ inside Diffusion of K+ through open K+ channels is critical for formation of resting potential: 140mM inside the cell; 5mM outside Na+ and other ions cant cross the membrane easily K+ outflow leads to a net negative charge INSIDE The buildup of negative charge is the major source of membrane potential o Modeling the Resting Potential: The flow of K+ outside continues until the electrical forces are balanced KCl Cl- cant pass = excess negative charge inside When it reaches equilibrium, the electrical gradient, balances the chemical gradient = NO FURTHER DIFFUSION OF K+ The magnitude of the membrane voltage at equilibrium for a particular ion is called the ions EQUILIBRIUM POTENTIAL Nernst equation: o Temperature = 37C o Ion net charge = 1+ Eion = 62mV(log[ion]outside/[ion]inside) The Eion for K+ is -90mV o less negative than the resting potential of a mammalian neuron This difference reflects the SMALL BUT STEADY MOVEMENT OF NA+ ACROSS THE FEW OPEN NA+ CHANNELS The concentration gradient of Na+ is OPPOSITE in DIRECTION to that of K+

Na+ diffuses INTO the cell (slowly); K+ diffuses OUT. Making the cell LESS negative o This (-) indicates that K+ is at equilibrium when the inside is 90mV more negative than the outside Membrane is only weakly permeable to other ions that are not K+ In an actual neuron, the resting potential is closer to EK than to ENa because there are more open K+ channels EK = -90mV (closer to -60, -80mV) ENa = +62mV Neither K+ or Na+ is ever at equilibrium in a resting neuron o Each ion has a current flow across the membrane Resting potential remains steady K+ and Na+ currents are equal and opposite (proportional) Concept Check 48.2 o Ions could flow from regions of high concentration to those of low concentration when there is an opposing electrical gradient (charge indicates where ions should go) of larger magnitude o Concentration gradient flow from more concentration, to less o More Na+ in (increase of permeability), more K+ out (decrease in permeability) would cause a cells membrane potential to shift from -70mV to -50mV o Na+ K+ pump is ESSENTIAL in the resting potential. Without it, the resting potential would be greatly reduced 48.3 Action potentials are the signals conducted by axons o Membrane potential changes in response to stimuli o Intracellular recording: record and graph changes as a function of time o Neurons contain GATED ION CHANNELS These open or close to stimuli Alters the membranes permeability to particular ions -> alters membrane potential o Hyperpolarization and depolarization: Opening potassium channels increase permeability to K+ Diffusion of K+ increases shifting m. potential towards EK

 Increase in magnitude of the membrane potential is called HYPERPOLARIZATION Makes the inside more negative (K ions of positive charge go out) Results from stimulus that increases OUTFLOW OF POSITIVE IONS or INFLOW OF NEGATIVE IONS Reduction in magnitude of membrane potential = DEPOLARIZATION Makes the inside less negative, more positive Often involves gated Na+ channels opening, letting more Na+ in Permeability to Na+ increases Membrane potential shifts to ENa o Graded potentials and Action potentials Shift in membrane potential caused by hyperpolarization or depolarization is called GRADED POTENTIAL: Its magnitude varies with the strength of the stimulus Large stimulus -> greater change in membrane potential Creates a small electrical current that leaks out of the neuron and flow along the membrane Decay with distance from source They have a big effect in generating nerve signals that travel along axons Depolarization shifts the membrane potential sufficiently Causes a massive change in voltage called ACTION POTENTIAL Constant magnitude and can regenerate in regions of the membrane that are close Action potentials can spread along axons This makes them well suited for transmitting signals through long distances Action potentials arise because some ion channels in neurons are VOLTAGE GATED ION CHANNELS

 Open or close when the membrane potential passes a certain level Depolarization opens voltage gated channels -> flow of Na+ in results in MORE depolarization Since Na+ channels are voltage gated, more Na+ channels open and there is a greater flow of current All of this causes POSITIVE FEEDBACK. MORE DEPOLARAZATION OPENS CHANNELS MORE NA+ IN MORE DEPOLAR MORE CHANNELS OPEN = MORE CURRENT FLOW This triggers a rapid opening of all voltage gated sodium channels and a marked change in m potential that defines action potential Depolarization occurs when membrane voltage goes over a THRESHOLD mammals: -55mV Once it starts, the action potential has a magnitude that is not affected by the strength of the stimulus Action potentials occur fully, or not at all. All or none response to stimuli Positive feedback loop triggers an action potential whenever a the membrane potential reaches the threshold Andrew Huxley and Alan Hodgkin: 1940s-1950s British Electrical recordings from giant neurons of squids o Generation of Action Potentials: A Closer Look Membrane depolarization opens voltage gated channels and K+ channels They respond independently and sequentially RESTING STATE: Membrane of axon is at resting potential, voltage gated sodium channels are mostly closed; some K+

channels are opened, but most voltage gated are closed DEPOLARIZATION: Stimulus depolarizes the membrane, some gated Na+ channels open but most voltage gated K+ channels are closed RISING PHASE OF A. POTENTIAL: Threshold is crossed, positive feedback cycle is initiated FALLING PHASE OF A. POTENTIAL: Voltage gated Na+ channels are inactivated by loop, Na+ inflow is halted, voltage gated K+ channels open, rapid outflow of K+ UNDERSHOOT: Permeability to K+ is higher than at rest, these K+ channels eventually close and the membrane goes back to resting potential. Na+ channels are unblocked but closed. Na+ channels are inactive during falling phase and beginning of undershoot THIS IS CALLED A REFRACTORY PERIOD If a second depolarizing stimulus occurs during this period, it will be UNABLE to trigger an action potential Refractory periods set a limit to how many action potentials can occur in a certain time It also insures that all signals travel through a same direction in an axon (cell body -> axon terminals) R. periods are due to inactivation of sodium channels Start of A. potential to end R. period = 2milisecs Frequency of A. Potentials varies in response to input Louder sounds = more frequent action potentials in neurons from ear to brain = more rapid response Gated ion channels and active potentials are key to all nervous system functions Mutations in genes that encode ion channel proteins can cause disorders that affect nerves, muscles, brain, or the heart.

 In the brain, epilepsy (seizures) In the skeletal muscles, myotonia (muscle spasms) o Conduction of Action Potentials Action Potentials are usually initiated in the axon hillock Na+ inflow in rising phase creates an electrical current that depolarizes a neighboring region in the axon membrane The depolarization is large enough to reach the threshold, which causes an initiation of action potential This is repeated through the length of the axon The magnitude and duration of the action potential remains constant Immediately behind the traveling zone of depolarization caused by Na+ inflow is a zone of repolarization caused by Na+ outflow In the repolarized zone, the Na+ channels remain inactivated The depolarization cannot spread behind This maintains the one-way flow of the signal in the axon o Evolutionary adaptations of axon structure Axon diameter affects the speed at which action potentials are conducted INCREASED AXON WIDTH increases conductance speed with less resistance to the current Giant axons in some invertebrates function in rapid behavioral responses Resistance to electrical current flow is inversely proportional to the width of a conductor Vertebrate axons are narrow but have ELECTRICAL INSULATION Causes the depolarizing current to spread further along the axon interior bringing more distant regions to the threshold sooner The insulation is called MYELIN SHEATH

 Produced by oligodendrocytes in the CNS and Schwann cells in the PNS; both glia Wrap axons in many layers of lipid membrane (poor conductors, good insulators) In myelinated axons, VOLTAGE GATED SODIUM CHANNELS are found in gaps in the myelin sheath called NODES OF RANVIER The extracellular fluid is in contact with the axon only in the Nodes of Ranvier Action Potentials are only generated in the regions between the nodes Inward current produced during the rising phase travels to the next node, where it depolarizes the membrane and regenerates the action potential This is called SALTATORY CONDUCTION Myelination causes space efficiency by making the best out of an axon of a small diameter o Concept Check Graded potentials only cause small electric currents by small shifts in membrane potential. These currents decay. Magnitude varies with stimulus strength. Action potentials occur when a threshold is reached by graded depolarization. There is a significant shift in membrane potential. Na+ moves inside at a higher rate, causing positive feedback which sends a signal regeneration in regions that are close. It transmits signals through a long distance In the axon. It is an all or none response. Not affected by stimulus strength once it has started. If myelin sheaths are defective, the bad insulation would slow down the rate in which signals are sent through the axon because action potential would not carry out at the same rate. Actions potentials would be generated slowly if a mutation caused gated sodium channels to remain inactive longer (refractory period) Repolarization = negative feedback 48.4 Neurons communicate with other cells at synapse

o Action potentials are not always transmitted from neurons to other cells, but information is transmitted at synapses o Electrical synapses: Contain GAP JUNCTIONS that allow electrical current to flow directly from one neuron to another Electrical synapses synchronize the activity of neurons responsible for RAPID, UNVARYING BEHAVIORS There are many electrical synapses in the vertebrate brain o The majority of synapses are CHEMICAL SYNAPSES: Release of chemical NEUROTRANSMITTERS by the presynaptic neuron At the terminal. the presynaptic neuron synthesizes the neurotransmitter and packages it into membrane-bound compartments called SYNAPTIC VESICLES When an action potential arrives at a terminal, it depolarizes the plasma membrane of presynaptic cell This allows Ca2+ to diffuse in through voltage gated channels The rise of Ca2+ concentration causes some of the synaptic vesicle to fuse with the membrane, releasing the neurotransmitter The neurotransmitter binds to ligand gated ion channels in the postsynaptic membrane, acting as a stimulus Synaptic transmission ends when: neurotransmitter diffuses out of the synaptic cleft is taken up by the synaptic terminal or by another cell is degraded by an enzyme Synaptic cleft gap that separates pre and post synaptic cell Diffusion time is short Neurotransmitter binds and activates a specific receptor in the membrane Info transfer is more readily modified in chemical synapses:

 Many factors affect the amount of neurotransmitter that is released or the responsiveness of the postsynaptic cell This alters an animals ability to alter its behavior as result to change and form learning and memory o Generation of Postsynaptic potentials The receptor protein that binds and responds to neurotransmitters is a LIGAND-GATED ION CHANNEL called a IONOTROPIC RECEPTOR Clusters in the membrane of the postsynaptic cell Binding of the neurotransmitter to a part of the receptor opens the channel and allows specific ions in o This is POSTSYNAPTIC POTENTIAL Postsynaptic potential is a graded potential in the postsynaptic cell When channels permeable to both K+ and Na+ open, the membrane potential is depolarized towards a value in between ENa and EK This depolarization brings the membrane potential towards THRESHOLD o EXCITATORY POSTSYNAPTIC POTENTIAL When channels are permeable for only K+ or Cland open, the postsynaptic membrane is HYPERPOLARIZED INHIBITORY POSTSYNAPTIC POTENTIAL Limit the duration of postsynaptic potentials Some neurotransmitters are transported back to be repackaged Or they are transported into glia to be metabolized as fuel Some are removed by diffusion and others are removed by enzymes that catalyze hydrolysis of the neurotransmitter o Summation of postsynaptic potentials The cell body and dendrites of one postsynaptic neuron may receive inputs from chemical synapses with hundreds or thousands of synaptic terminal:

 Many, many signals The magnitude of postsynaptic potential in one synapse varies with many factors: amount of neurotransmitters released postsynaptic potential becomes smaller with distances (graded potential) When an EPSP reaches an axon hillock, it is too small to trigger an action potential in a postsynaptic neuron 2 EPSPs from a same synapse together can cause TEMPORAL SUMMATION EPSPs produced at the same time by different synapses can add to form SPATIAL SUMMATION Several EPSPs can combine to depolarize the membrane at the axon hillock to threshold causing Action Potential This also applies to IPSPs: Two or more occurring almost simultaneously, in the same region, or in rapid succession at the same synapse have a larger hyperpolarization effect than just one IPSP can counter the effect of an EPSP This interplay between inhibitory and excitatory is the essence of integration The axon hillock is the neuron integrating center The membrane potential here represents the effects of all EPSPs and IPSPs summed When it reaches a threshold, action potential is started and travels to the synaptic terminals After the refractory period, the neuron may again produce another action potential if threshold is reached o Modulated Signaling at Synapses There are synapses where the receptor for the neurotransmitter is not part of the ion channel The neurotransmitter binds to a METABOTROPIC RECEPTOR

 the opening or closing depends on one or more metabolic step Involves a second messenger Binding activates a signal transduction pathway in the postsynaptic cell involving a second messenger The effects of this system are slower, but last longer Second messengers modulate responsiveness of postsynaptic neurons Ex. altering the number of open potassium channels Signals transduction pathways: cyclic AMP (cAMP) as a second messenger o Activates protein kinase A which phosphorylates specific ion channels proteins in the postsynaptic membrane, causing them to open and close Because of the amplifying effect of signal transduction pathways: o the binding of a neurotransmitter to a metabotropic receptor can open or close many channels o Neurotransmitters: 100 neurotransmitters in groups: acetylcholine amino acids biogenic amines neuropeptides gases The response to these depends on the particular kind of receptor expressed by the postsynaptic cell 1 neurotransmitter can bind to a dozen or more ionotropic or metabotropic receptors 1 neurotransmitter can inhibit a postsynaptic cell expressing one receptor and excite one expressing another receptor o Acetylcholine:

 Functions including muscle stimulation, memory formation, and learning Classes of acetylcholine receptors: ligand-gated ion channel neuromuscular junction: where motor neurons synapse with skeletal muscle cells Ion channel opens and produces an EPSP. (excitatory) Terminated by acetylcholinesterase, that hydrolyses the neurotransmitter (enzyme) Can bind nicotine Metabotropic receptor at the CNS and heart : Activates signal pathway where G proteins inhibit adenylyl cyclase and open K+ channels in the muscle cell membrane Reduce the rate at which the heart pumps (inhibitory) Natural and synthetic toxins can disrupt acetylcholine neurotransmission Nerve gas, sarin, inhibits acetylcholinesterase This causes a buildup of acetylcholine -> paralysis -> death Botulium toxin, created by bacteria inhibits presynaptic release of acetylcholine This causes food poisoning which can be fatal because muscles needed for breathing fail to contract when acetylcholine is blocked Botulinum toxin is Botox which is used to minimize wrinkles by blocking transmission at synapses that control facial muscles o Amino Acids Active in CNS and PNS In the CNS, the amino acid GLUTAMATe is the most common neurotransmitter: When it binds to ligand-gated ion channels, it is EXCITATORY Formation of long term memory GAMMA-AMINOBUTYRIC ACID (GABA) is at most INHIBITORY synapses in the brain Binding GABA increases membrane permeability to Cl- resulting in an IPSP.

 Valium (diazepam) reduces anxiety through binding to a site on a GABA receptor GLYCINE acts as an INHIBITORY synapse in part of the CNS outside of the brain Binds to an ionotropic receptor inhibited by strychnine, a chemical used in rat poison o o Biogenic Amines Synthesized from amino acids Include NOREPINEPHRINE, made from tyrosine EXHITATORY neurotransmitter in the PNS Also acts as a hormone outside the nervous system DOPAMINE, made from tyrosine SEROTONIN, made from tryptophan Both are released in the brain and affect sleep, mood, attention, and learning LSD and mescaline produce hallucinatory effects by binding to brain receptors for serotonin and dopamine Parkinsons disease is associated with lack of dopamine in the brain Depression is treated with drugs that increase concentration of biogenic amines in the brain (Prozac, serotonin reuptake) o Neuropeptides: Short chains of amino acids Operate via METABOTROPIC RECEPTORS Produced by cutting much larger proteins SUBSTANCE P is a key EXCITATORY neurotransmitter that mediates our perception of pain ENDORPHINS are natural analgesics, decreasing pain Candace Pert and Solomon Snyder discovered endorphins Endorphins are produced in the brain during times of physical or emotional stress They relieve pain, they decrease urine output, depress respiration, produce euphoria, and other emotional effects

 Opiates mimic endorphins and produce similar effects o Gases Some neurons in vertebrates release dissolved gases NITRIC OXIDE (NO) Act as local regulators Produces erections during arousal Viagra increases the ability to achieve and maintain an erection by inhibiting an enzyme that terminates the action of NO NO is not stores in cytoplasmic vesicles but is synthesized on demand It diffuses into neighboring target cells, produces a change, and is broken down NO works like hormones stimulating the enzyme to synthesize a second messenger that directly affects cellular metabolism CO: Vertebrates produce small amounts of CO, some of which act as neurotransmitters Generated by hemo oxigenase (brain and PNS) CO regulates the release of hypothalamic hormones in the brain In the PNS, it is an INHIBITORY neurotransmitter that hyperpolarizes the membrane of intestinal smooth muscle cells o Concept Check 48.4 One neurotransmitter can bind to different receptors and have one effect in one receptor and a different one in another. It could act as an IPSP in one and an EPSP in another. Toxins that inhibit the acetylcholinesterase would create a buildup of acetylcholine. There would be a great amount of at a longer length of time EPSPs because acetylcholine would spend more time in the synaptic cleft If a drug mimicked the activity of GABA, this would cause an inhibitory synapse in the brain, decreasing brain activity

 Membrane fusion is common in fertilization and neurotransmitter release KEY CONCEPT QUESTIONS: o Severing an axon would prevent information from being transmitted away from the cell body along the axon and getting to a postsynaptic cell o If you change a single neuron to a solution lacking NA+, the resting potential would not change or would become slightly more negative (hyperpolarization). There are vey few open Na+ channels in a resting neuron o Positive feedback is responsible for the rapid opening of voltage-gated sodium channels m causing a rapid inflow of sodium ions responsible for the rising phase of action potential. As the membrane potential becomes positive, voltage gated K+ channels open in a form of negative feedback to start the falling phase of the action potential. o 1 neurotransmitter can have many receptors with different locations and activities. Drugs that target receptors are more specific and fewer undesirable side effects.