Question: How do neurons transmit signals?

1. Question: How do neurons transmit signals?

2. Transmitting signals • First neurons have to set up the membrane potential; separation of charge across the plasma membrane (potential energy) • Like a battery with + and - ends, once connected, you get energy (voltage)

3. Ion pumps and ion channels Membrane potential-the charge difference between a cell’s cytoplasm (inside) and the extracellular fluid (outside), due to a differential distribution of ions In neurons, the membrane potential is typically between -60 and -80 mV when the cell is NOT transmitting a signal, this is called the resting potential The inside of the cell is negative relative to the outside of the cell, sets up an electrical gradient

4. Measurement of the resting membrane potential Outside High [Na+] Inside High [K+] 2 Electrodes: one placed inside cell, one outside cell to measure the voltage caused by the separation of charges across the cell membrane

5. Question:How does the neuron set up the membrane potential (separation of charge)?

6. The basis of the membrane potential Maintaining the Resting Membrane Potential requires Energy! [A-] are large negative ions like phosphate (PO4-3) A separation of charge (voltage) develops across the membrane, the membrane is more permeable to K+ which passively move out, while Na+ moves in However there is a pump to actively move K+ in and move Na+ out electrical gradient opposite direction of concentration gradient, requires energy to move ions against their conc. gradient

7. The Na+ and K+ gradients are maintained by the sodium-potassium pump This transport system pumps ions against a steep concentration gradient (requires ATP) Move 3 Na+ OUT for every 2 K+ IN (see movie)

8. The basis of almost all electrical signals in the nervous system: the membrane potential can change from its resting value when the membrane’s permeability to a particular ion changes

9. Ion Channels • Ungated – always open • Gated – open or close in response to stimulus • Stretch Gated (Knee Jerk Reflex) • Ligand (chemically) Gated (found in synapses) a specific neurotransmitter binds to a receptor to open ion channels • Voltage Gated*- open or close when membrane potential changes. Found in axons, dendrites, cell bodies.

10.  The knee-jerk reflex Sensory neurons convey the information to the spinal cord. Sensors detect a sudden stretch in the quadriceps. The sensory neurons communicate with motor neurons that supply the quadriceps. The motor neurons convey signals to the quadriceps, causing it to contract and jerking the lower leg forward. 3 1 6 2 4 5 Cell body of sensory neuronin dorsal root ganglion Gray matter Sensory neurons from the quadriceps also communicate with interneuronsin the spinal cord. Quadricepsmuscle White matter Hamstringmuscle The interneurons inhibit motor neurons that supply the hamstring (flexor) muscle. This inhibition prevents the hamstring from contracting, which would resist the action of the quadriceps. Spinal cord(cross section) Sensory neuron Motor neuron The reflex is initiated by tapping the tendon connected to the quadriceps (extensor) muscle. Interneuron Reflexes are the body’s automatic response to stimuli

11. Stimuli that open voltage-gated ion channels may result in changes in the membrane potential

12. Changes in the membrane potential Hyperpolarization is an increase in the magnitude of the membrane potential (inside of cell becomes more negative), may be due to the opening of gated K+ channels Depolarization is a reduction in the magnitude of the membrane potential, may be due to the opening of gated Na+ channels These are graded potentials, the magnitude of the hyper- or depolarization varies with the strength of the stimulus

13. Action potentials In most neurons, depolarizations are graded only up to a certain point-called the threshold If a stimulus produces a depolarization that reaches the threshold, this triggers a different type of response called an action potential

14. Action potentials are: It has a magnitude that is independent of the strength of the triggering stimulus 2. Requires a threshold stimulus for activation 3. They are all-or-none 4. They are followed by a refractory period(“downtime”)

15. Graded potentials A stronger depolarization stimulus past the threshold will trigger an action potential (all or none) Action potentials are how nerve impulses are created

16.  Role of voltage-gated ion channels in the generation of an AP +50 Actionpotential 0 Membrane potential (mV) Threshold Threshold –50 Resting potential –100 Time Extracellular fluid Activationgates Potassiumchannel Na+ 1 1 3 4 5 1 2 +  +  +  +  +  +  +  + +  + +  + +  + Plasma membrane –  –  –  –  –  –  –  – –  – –  – –  – Undershoot Cytosol Inactivationgate Sodiumchannel K+ Resting state The activation gates on the Na+ and K+ channels are CLOSED, resting potential

17. +50 Actionpotential Na+ Na+ 0 Membrane potential (mV) Threshold Threshold –50 K+ Resting potential –100 Time Depolarization Extracellular fluid Activationgates Potassiumchannel Na+ 1 1 2 2 4 5 3 1 +  +  +  +  +  +  +  + +  + +  + +  + +  + +  + +  + +  + Plasma membrane –  –  –  –  –  –  –  – –  – –  – –  – –  – –  – –  – –  – Cytosol Inactivationgate Sodiumchannel K+ Resting state  The role of voltage-gated in the generation of an action potential (layer 2) A stimulus opens the activation gates on some Na+ channels, influx of Na+ depolarize the membrane, if reach threshold, trigger an AP

18. Na+ Na+ K+ Rising phase of the action potential +50 Actionpotential Na+ Na+ 0 Membrane potential (mV) Threshold Threshold –50 K+ Resting potential –100 Time Depolarization Extracellular fluid Activationgates Potassiumchannel Na+ 4 3 5 1 1 2 2 1 3 +  +  +  +  +  +  +  + +  + +  + +  + +  + +  + –  – –  – –  – –  – +  + +  + Plasma membrane –  –  –  –  –  –  –  – +  + +  + +  + +  + –  – –  – –  – –  – –  – –  – –  – Cytosol Inactivationgate Sodiumchannel K+ Resting state  The role of voltage-gated ion channels in the generation of an action potential (layer 3) Rising phase of action potential -most Na+ channels open more Na+ move IN

19. Na+ Na+ Na+ Na+ K+ K+ Falling phase of the action potential Rising phase of the action potential +50 Actionpotential Na+ Na+ 0 Membrane potential (mV) Threshold Threshold –50 K+ Resting potential –100 Time Depolarization Extracellular fluid Activationgates Potassiumchannel Na+ 2 4 3 3 2 1 4 5 1 1 +  +  +  +  +  +  +  + +  + +  + +  + +  + +  + +  + +  + +  + +  + –  – –  – –  – –  – +  + +  + Plasma membrane –  –  –  –  –  –  –  – +  + +  + +  + +  + –  – –  – –  – –  – –  – –  – –  – –  – –  – –  – –  – Cytosol Inactivationgate Sodiumchannel K+ Resting state The role of voltage-gated ion channels in the generation of an action potential (layer 4) Most Na+channels close K+ channels open, K+ moves OUT of neuron

20. Na+ Na+ Na+ Na+ K+ K+ Falling phase of the action potential Rising phase of the action potential +50 Actionpotential Na+ Na+ 0 Membrane potential (mV) Threshold Threshold –50 K+ Resting potential –100 Time Depolarization Na+ Na+ Extracellular fluid Activationgates Potassiumchannel Na+ 1 2 1 4 4 3 3 2 1 5 5 +  +  +  +  +  +  +  + +  + +  + +  + +  + +  + +  + +  + +  + +  + +  + +  + +  + +  + –  – –  – –  – –  – +  + +  + K+ Plasma membrane –  –  –  –  –  –  –  – +  + +  + +  + +  + –  – –  – –  – –  – –  – –  – –  – –  – –  – –  – –  – –  – –  – –  – –  – Undershoot Cytosol Inactivationgate Sodiumchannel K+ Resting state  The role of voltage-gated ion channels in the generation of an action potential (layer 5) Some K+ activation gates are open As these close-return to resting pot.

21. The Action Potential Results from changes in permeability to different ions First there is an inward rush of sodium ions, followed by an outflow of potassium ions.

22. AP need to carry information along axons and sometimes over great distances (from your toes to your brain) To function as a long-distance signal, action potentials have to regenerate itself along the axon

23.  Conduction of an action potential Axon Actionpotential – – + + + + + + An action potential is generated as Na+ flows inward across the membrane at one location. 1 + + – – – – – – Na+ – – – – – – + + – – + + + + + + Actionpotential The depolarization of the action potential spreads to the neighboring region of the membrane, re-initiating the action potential there. To the left of this region, the membrane is repolarizing as K+ flows outward. 2 K+ – – + + + + + + – – + – – – + – Na+ – – – – – – + + – – + + + + + + K+ Actionpotential The depolarization-repolarization process isrepeated in the next region of the membrane. In this way, local currents of ions across the plasma membrane cause the action potential to be propagated along the length of the axon. K+ – – – – + + + + 3 + + + + – – – – Na+ – – – + + – + + – – + + – – + + K+

24. Conductance of action potentials In myelinated axons, voltage-gated Na+ and K+ channels are concentrated at the gaps in the myelin sheath-Nodes of Ranvier Saltatory conduction-the action potential appears to jump along the axon from node to node -this can transmit action potentials at speeds up to 120 m/sec

25. Transmitting the signal from cell to cell Synapse - junction between a neuron and another cell • 1. Electrical synapse • (cells almost in contact) • -Very Fast • -Electrical current can move from nerve cell to nerve cell via channels • called Gap Junctions • 2. Chemical synapse • (cells separated by small space called clefts) • -slower • -chemical messenger diffuses across clefts between pre and post • synaptic neurons

26. Electrical synapse Gap junctions provide cytoplasmic channels from one cell to an adjacent cell Gap junctions are necessary for communication between cells They help coordinate certain rapid, sterotyped behaviors Hormone-secreting neurons within the mammalian hypothalamus are connected by electrical synapses. This arrangement ensures that all cells fire action potentials at about the same time, thus facilitating a burst of hormone secretion into the circulation.

27. Chemical synapse Chemical synapses involve the release of a chemical neurotransmitter by the signaling neuron -The neurotransmitters are released into the synapse in vesicles Neurotransmitters bind to receptors on the receiving neuron act like a lock and key, only one type of neurotransmitter can fit into the lock of the receptor to open the channel

28. Chemical Synapse When an action potential reaches the terminal and depolarizes the membrane it: 1. Opens voltage-gated Ca++ channels in membrane influx of Ca++ 2. This causes the synaptic vesicles to fuse with the membrane 3. Release of neurotransmitter into synaptic cleft 4. The neurotransmitter binds to receptor of ligand (chemically)-gated ion channels in postsynaptic membrane, open channels

29. Chemical synapse Postsynaptic cell Presynapticcell Na+ Synaptic vesiclescontainingneurotransmitter Neuro-transmitter K+ Presynapticmembrane Postsynaptic membrane Ligand-gatedion channel Voltage-gatedCa2+ channel Ca2+ Postsynaptic membrane 4 Synaptic cleft Ligand-gatedion channels 1 2 3 5 6 NOTE: only allows one way travel!! Neurotransmitter binds specifically to a receptor site of the postsynaptic cell, causing ion channels to open

30. Direct synaptic transmission is when the neurotransmitter binds directly to chemically-gated ion channels in postsynaptic cell, this opens the ion channels, if Na+ moves into the cell, this depolarizes the cell, bringing it toward the threshold, these are call excitatory postsynaptic potentials (EPSPs), if it brings it further away then it is inhibitory (IPSP)

31. multiple neurotransmitters some excitatory some inhibitory

32. EPSPs add together in an effect called temporal summation

33. Postsynaptic potentials Postsynaptic potentials are different from action potentials in that they are graded, their magnitude varies with a number of factors, including the amount of neurotransmitter released They also are different in that they usually do NOT regenerate themselves as they spread along the membrane of a cell (they become smaller with distance from the synapse) Multiple EPSPs can depolarize the membrane and cause the postsynaptic neuron to produce an action potential

34. Nervous System • Neurotransmitter Molecules • At least 50 have been identified • Two well-known neurotransmitters: • Acetylcholine (ACh) • Norepinephrine (NE) • After a neurotransmitter has initiated a response it is removed from the synaptic cleft • Enzymes may inactivate the neurotransmitter the enzyme acetylcholinesterse (AChE) breaks down ACh • The neurotransmitter may be reabsorbed by the presynaptic membrane • Prevents continuous stimulation (or inhibition) of postsynaptic (receiving) membranes

35. Events leading to conduction of a nerve impulse • Neuron membrane is at resting potential • Threshold stimulus is received • Sodium channels in the initial zone are open • Sodium moves inward, depolarizing the membrane • Potassium channels open, repolarizing the membrane • Causes depolarization of neighboring area • Wave of action potentials travel the length of the axon as a nerve impulse

36. Question: What happens when things go wrong in the nervous system?

37. Alzheimer Disease • Characterized by gradual loss of memory and can lead to inability to perform daily activities • Researchers have discovered that some families with a 50% chance of AD, have a genetic defect of chromosome 21 • Characterized by abnormally structured neurons (protein envelops the axon branches) and a reduced amount of ACh.

38. Treatment for AD • Cholinesterase inhibitors (Aricept) work at the neuron synapses to slow the activity of the enzyme that breaks down acetylcholine (ACh) • Memantine (Namenda) that blocks exoitotoxicity, the tendency for diseased neurons to self-destruct

39. Multiple Sclerosis Chronic, progressive illness that affects the nerves of the brain, spinal cord, and optic nerves (CNS) Autoimmune disorder in which myelin (covering nerves) is the major target of an immune attack. When myelin or the nerve fiber is destroyed or damaged, the ability of the nerves to conduct electrical impulses to and from the brain is disrupted, and this produces the various symptoms of MS. (blurred vision, paralysis, loss of coordination) There is NO cure for MS

40. multiple sclerosis T cells (immune-system WBC) attack the myelin sheath In multiple sclerosis, T-cells attack the myelin sheath, resulting in progressive loss of body function http://www.nlm.nih.gov/medlineplus/muliplesclerosis.html

41. Bee sting Therapy (apitherapy) Alternative treatment for MS and other disorders The healing potency of bee venom is initiated after a sting, when it stimulates the adrenal glands to produce cortisol, a natural human hormone that has anti-inflammatory properties. In addition, Bee sting therapy jump starts the immune system to produce a healing response through the hypothalamus, pituitary, and adrenal glands, and spurs the production of endorphins, the body's natural pain killer. bee venom also has the neurotransmitters dopamine, serotonin and norepinephrine, which along with the peptide apamin, facilitate nerve transmission and healing in conditions involving nerve disorders. http://www.beewelltherapy.com/?gclid=CJG50YXh0YoCFRw8gQod80zpcw http://www.mymultiplesclerosis.co.uk/beevenom.html

42. Neurotoxins • Neurotoxins are toxins that act specifically on nerve cells • They usually interact with membrane proteins such as ion channels • Many of the venoms and other toxins that organisms use as a defense against vertebrates are neurotoxins

43. Batrachotoxin • One of the most potent toxins known • It acts directly on sodium ion channels involved in action potential generation in the peripheral nervous system (PNS) • Batrachotoxin kills by permanently blocking nerve signal transmission to the muscles (especially of the heart) • There is no known antidote

44. Tetrodotoxin (TTX) • TTX a potent neurotoxin from pufferfish which blocks action potentials in nerves by binding to the pores of the voltage-gated, fast sodium channels in nerve cell membranes in human myocytes (contractile cells of the muscles), thereby inhibiting their contraction • The poisoned individual therefore dies because the muscles are effectively paralyzed. Can lead to respiratory failure. • There is no effective antidote