1. Dr Gihan Gawish King Saud University Riyadh Saudi Arabia Saudi Arabia Dr. Gihan Gawish Assistant Professor

2. Dr Gihan Gawish The fourth major class of vertebrate tissue.

3. Dr Gihan Gawish The function of the nervous tissue is in communication between parts of the body. It is composed of neurons, which transmit impulses, and the neuroglia, which assist propagation of the nerve impulse as well as provide nutrients to the neuron. All nervous tissue of an organism makes up its nervous system, which includes the brain, spinal cord, and nerves throughout the organism. Nervous tissue is made of nerve cells that come in many varieties, all of which are distinctly characteristic by the axon or long stem like part of the cell that sends action potential signals to the next cell.

4. Dr Gihan Gawish The Nervous System The body’s control centre and communication network

5. Dr Gihan Gawish The Nervous System Functions Sensation – senses changes in the environment: internal and external Integration – interprets the changes Response – initiates a response through: muscle contraction or glandular secretion

6. Dr Gihan Gawish The Nervous System

7. Dr Gihan Gawish Organization of the Nervous System Central nervous system Brain & spinal cord. Integrative & control centers. Peripheral nervous system Cranial & spinal nerves. Communicates between CNS and rest of body. Sensory (afferent division) Impulse from receptor to CNS. Motor (efferent) division Impulse from CNS to effector. Autonomic nervous System -to visceral organs. Somatic nervous System -to muscles Sympathetic Division “Excites” Parasympathetic Division “Retards”

8. Dr Gihan Gawish The Nervous System: Histology Characteristics of nerve tissue: Irritability – ability to respond to stimuli Conductivity – ability to carry electrical impulses

9. Dr Gihan Gawish Types of Cells Neuroglia – supportive and protective cells, found mainly in the CNS Neurons – the functional portion of the nervous system; specialized for impulse conduction.

10. Dr Gihan Gawish Structure of the Neuron Consists of: A Cell Body – contains nucleus, mitochondria, no reproductive apparatus Processes Dendrites: highly branched extensions of the cell body. Conduct impulses towards the cell body Axon: a single long process. Conducts impulses away from the cell body.

11. Dr Gihan Gawish Neurons (nerve cell)

12. Dr Gihan Gawish Structure of the Neuron Myelin Sheath – a white, multi layered, fatty covering for some nerve processes. – arranged in segments, separated by Nodes of Ranvier (enables salutatory conduction) Function Insulation of nerve process Increased speed of conduction Neurilemma – outer layer of myelin sheath – essential for regeneration

13. Dr Gihan Gawish Myelin Sheath & Neurilemma: Formation

14. Dr Gihan Gawish Location of Neuron Structures Cell Bodies – usually arranged in functional groups call nuclei (CNS) or ganglia (PNS) Processes – arranged in bundles called tracts (CNS) or nerves (PNS) Synapse – neuronal junction

15. Dr Gihan Gawish Classification of Neurons based on direction of impulse Afferent (sensory) neurons – conduct impulses towards the CNS Efferent (motor) neurons – conduct impulses away from the CNS Internuncial (association) Neurons –carry impulses between neurons within the CNS (may be either sensory or motor)

16. Dr Gihan Gawish

17. Membrane transport The lipid bilayer of biological membranes is intrinsically impermeable to ions and polar molecules.

18. Dr Gihan Gawish Transport processes have several important roles: Regulate cell volume Maintain the intracellular pH and and ionic composition (enzyme activity) Extract the concentrate metabolic fuels (toxic substance). Generate ionic gradient that are essential for the excitability of nerve and muscle.

19. Dr Gihan Gawish Permeability is conferred by two classes of membrane proteins, pumps and channels. Pumps use a source of free energy such as ATP or light to drive the thermodynamically uphill transport of ions or molecules. Pump action is an example of active transport. Channels, in contrast, enable ions to flow rapidly through membranes in a downhill direction. Channel action illustrates passive transport, or facilitated diffusion.

20. Dr Gihan Gawish Pumps Pumps are energy transducers in that they convert one form of free energy into another. ATP + H O ADP + P + H 2 i +Na, K, Mg ++ 2+2+ Na K ATPase + +

21. Dr Gihan Gawish Discovery of the active transport system for sodium and potassium ions Most animal cells have a high concentration of K ions and a low concentrations of Na ions relative to the external medium. These ionic generated by a specific transport system called pump More than a third of the ATP consumed by a resting animals is used to pump these ions.

22. Dr Gihan Gawish Skou surmised that: 1)The Na K ATPase is present whereever Na and K ions are actively transported. 2)Both Na K ATPase and the pump are associated with the plasma membrane. 3)Both Na K ATPase and the pump are oriented in the same way in the plasma membrane

23. Dr Gihan Gawish 4. Variations of the concentrations of Na and K ions have parallel effects on the ATPase activity and on the rate of transport of these ions 5. The pump can be reversed under suitable ionic conditions

24. Dr Gihan Gawish 6. The Na ions must be inside, whereas K ions must be outside to activate the ATPase and to be transported across the membrane ATP ADP + Pi Vanadate inhibits from the inside Na + K + Cardiotonic steroid (ouabain& digitoxigenin) must be outside to inhibit

25. Dr Gihan Gawish Action Potentials A nerve impulse is an electrical signal produced by the flow of ions across the plasma membrane of a neuron and is the fundamental means of communication in the nervous system. The interior of a neuron, like that of most other cells, has a high concentration of K+ and a low concentration of Na+. These ionic gradients are generated by an ATPdriven pump Action potential is a rapid, transient change in membrane potential that can be transmitted over long distances

26. Dr Gihan Gawish Resting state In the resting state, the membrane potential is -60 mV. A nerve impulse, or action potential, is generated when the membrane potential is depolarized beyond a critical threshold value (i.e., from -60 to -40 mV). The membrane potential becomes positive within about a millisecond and attains a value of about +30 mV before turning negative again. This amplified depolarization is propagated along the nerve terminal

27. Dr Gihan Gawish Depolarization: when the membrane potential becomes more positive than the resting membrane potential Hyperpolarization: when the membrane potential becomes less positive (more negative) than the resting membrane potential threshold stimulus (“threshold”): a minimum stimulus required to elicit an action potential

28. Dr Gihan Gawish Action potentials arise from large, transient changes in the permeability of the axon membrane to Na + and K + ions Two kinds of voltage-sensitive channels, one selectively permeable to Na+ and the other to K+, were defined. The conductance of the membrane to Na+ changes first. Depolarization of the membrane beyond the threshold level leads to an opening of Na+ channels. Sodium ions begin to flow into the cell because of the large electrochemical gradient across the plasma membrane.

29. Dr Gihan Gawish The entry of Na+ further depolarizes the membrane, and so more gates for Na+ are opened. This positive feedback between depolarization and Na+ entry leads to a very rapid and large change in membrane potential, from about -60 mV to +30 mV in a millisecond

30. Dr Gihan Gawish Sodium channels spontaneously close and potassium channels begin to open at about this time Consequently, potassium ions flow outward, and so the membrane potential returns to a negative value. The resting level of -60 mV is restored in a few milliseconds as the K+ conductance decreases to the value characteristic of the unstimulated state. Only a very small proportion of the sodium and potassium ions in a nerve cell, of the order of one in a million, flows across the plasma membrane during the action potential. Clearly, the action potential is a very efficient means of signaling over large distances.

31. Dr Gihan Gawish Membrane Potential. Depolarization of an axon membrane results in an action potential. Time course of (A) the change in membrane potential and (B) the change in Na+ and K+ conductances.

32. Dr Gihan Gawish The Action Potential cont’d...

33. Dr Gihan Gawish Poisons of the Na Channel Tetrodotoxin, an organic compound isolated from the puffer fish, binds to sodium channels with great avidity. The lethal dose of this poison for an adult human being is about 10 ng. A puffer fish is regarded as a culinary delicacy in Japan +

34. Dr Gihan Gawish Poisons of the Na Channel A common feature of tetrodoxotin is the presence of guanido group. The densities of Na ions channels in a variety of excitable membranes have been determined by measuring the binding of highly radioactive tetrodoxotin. Tetrodotoxin +

35. Dr Gihan Gawish Na channel was purified on the basis of its ability to bind a specific neurotoxin. 1.The sodium channel was first purified from the electric organ of electric eel, which is a rich source of the protein forming this channel. Unmyelinated nerve fibers have 20/µm of Na channels. Axonal membrane has 2000A apart of Na channels. Myelinated nerve fibers (nodes of Ranivor) have 10 /µm of Na channels. + 4 + + + O

36. Dr Gihan Gawish Na channel was purified on the basis of its ability to bind a specific neurotoxin 2.The isolated protein is a single chain of 260 kd. 3.The availability of purified protein enabled to clone and sequence the cDNA for the sodium channel +

37. Dr Gihan Gawish The Sodium Channel. 1.The Na+ channel is a single polypeptide chain with four repeating units (I - IV). 2.Each repeat probably folds into six transmembrane helices. 3.The loops (shown in red) between helices 5 and 6 of each domain form the pore of the channel.

38. Dr Gihan Gawish Neurotransmitters Nerve cells interact with other nerve cells at junction called synapes. Nerve impulses are communicated across most synapses by small, diffusible molecules called neurotransmitters, of which one is acetylcholine

39. Dr Gihan Gawish Criteria of an established Criteria of an established Neurotransmitters 1.Microinjection of the proposed transmitter into the synaptic cleft must elicit the response as dose excitation of the presynaptic nerve. 2.The presynaptic nerve terminals must be rich in this neurotransmitter. 3.The presynaptic nerve must release the postulated transmitter at the right time and in a quantity sufficient to act on the post synaptic nerve

40. Dr Gihan Gawish 1. Acetylcholine is a neurotransmitters Acetylcholine is not an amino acid or an amino acid derivative. Its synthesized by the enzyme choline acetyltransferase Acetyl cholinesterase is present both in the nerve terminal cytoplasm and extracellularly, in the synaptic cleft. When acetylcholine is broken down by extracellular cholinesterase, the choline is transported back into the nerve terminal, where it is recycled back into acetylcholine. This reuptake of choline back into the nerve terminal is important in terms of replenishing the supply of acetylcholine, because neurons cannot synthesize choline themselves.

41. Dr Gihan Gawish 1. Acetylcholine is a neurotransmitters Choline Acetylcholine H Acetyl CoA Nerve terminal cytoplasm Synaptic cleft

42. Dr Gihan Gawish 1-1. Cholinergic Synapse The presynaptic membrane of a synapse is separated from the postsynaptic membrane by a gap of about 50 nm, called the synaptic cleft. The end of the presynaptic axon is filled with synaptic vesicles, each containing about 10 acetylcholine molecules Cholinergic Synapse 4

43. Dr Gihan Gawish Acetyl open cation gates in the postsynaptic membrane The arrival of a nerve impulse leads to the synchronous export of the contents of some 300 vesicles, which raises the acetylcholine concentration in the cleft from 10 nM to 500 mM in less than a millisecond. The binding of acetylcholine to the postsynaptic membrane markedly changes its ionic permeabilities

44. Dr Gihan Gawish Acetyl open cation gates in the postsynaptic membrane The conductance of both Na + and K + increases greatly within 0.1 ms, leading to a large inward current of Na + and a smaller outward current of K +. The inward Na+ current depolarizes the postsynaptic membrane and triggers an action potential Acetylcholine opens a single kind of cation channel, which is almost equally permeable to Na + and K +. This change in ion permeability is mediated by the acetylcholine receptor.

45. Dr Gihan Gawish Acetylcholine depolarizes the postsynaptic membrane by increasing the conductance of Na+ and K+.

46. Dr Gihan Gawish Ligand-gated channel. The acetylcholine receptor is the best-understood ligand-gated channel. The activity of a single such channel is graphically displayed in patch-clamp recordings of postsynaptic membranes of skeletal muscle The addition of acetylcholine is followed by transient openings of the channel. The current, i, flowing through an open channel is 4 pA (picoamperes) when the membrane potential, V, is -100 mV. An ampere is the flow of 6.24 × 1018 charges per second. Hence, 2.5 × 107 ions per second flow through an open channel.

47. Dr Gihan Gawish Patch-Clamp Recordings of the Acetylcholine Receptor Channel. 1. Patch-clamp recordings illustrate changes in the conductance of an acetylcholine receptor channel in the presence of acetylcholine. 2.The channel undergoes frequent transitions between open and closed states.

48. Dr Gihan Gawish Neurotransmitters 2. Catecholamine Neurotransmitters 2. Catecholamine Pathway of the synthesis of catecholamine neurotransmitters

49. Dr Gihan Gawish Neurotransmitters 3. γ Aminobutyrat γ Aminobutyrat Synthesis and inactivation of γ Aminobutyrat