Neurophysiology, Neurotransmitters and the Nervous System

1. Neurophysiology, Neurotransmitters and the Nervous System

2. The Neuron The nervous system is made of nerve cells or neurons and glial cells. Glial cells are not excitable and provide metabolic and physical support for the neurons. 90% of the cells are glial cells. Neurons are excitable and control behavior

3. Neuron

4. Resting potential

5. Resting potential There is a potential difference between the inside and outside of as membrane. The inside is about -70 mv relative to the outside.

6. Resting Potential The resting potential is caused by an uneven distribution of ions (electrically charged molecules) of potassium (K+) and sodium (Na+) and chloride (Cl-). This is caused by Na+/K+ ion pumps that move 3 Na+ ions out of the cell for every 2 K+ ions it moves in. Therefore there are more +ions outside the cell than inside and the inside is negatively charged with respect to the outside

7. Ion pump

8. Resting potential An ion channel is a combination of large protein molecules that cross the membrane and allow specific ions to pass through at a specific rate, These allow enough leakage of ions to mostly neutralize the effect of the ion pump, but

9. Ion channels

10. Resting potential • Forces maintaining the resting potential • Diffusion pressure – molecules want to move from areas of high concentration to areas of low concentration. • Electrostatic charge – ions with like charge are repelled and ions with a different charge are attracted. • Operation of ion pumps and ion channels.

11. Action potential • Anything that alters the functioning of the ion channels can change the resting potential. • If changes cause the resting potential to be reduced, this is called depolarization. • If the change causes an increase in the resting potential, this is caused hyperpolarization.

12. Action Potential • We can insert an electrode across a membrane and cause depolarization, i.e., we can depolarize the cell. • If we reduce the resting potential past a threshold, the resting potential breaks down.

13. Action potential • Voltage gated ion channels open and let Na+ into the cell. They are driven into the cell because of diffusion gradient and electrostatic charge. • This causes the resting potential to reverse, i.e., the inside the cell becomes positive. • Now the Na+ ion channels close and the K+ channels open and the K+ ions are driven out of the cell because of their concentration gradient and electrostatic charge. • Finally the K+ channels close and the ion pumps kick in and the resting potential returns to normal.

14. Action potential

15. All or None Law • Action potentials when they occur are always the same. • Once the process is initiated, it must run its course and nothing can stop it or change it

16. Transmission of action potentials along a membrane • When an action potential occurs at one place on the membrane of an axon, the surrounding membrane is depolarized past threshold causing an action potential. This depolarizes the neighboring membrane, etc. • Action potentials sweep across a membrane as fast as 100m/sec

17. Transmission of action potentials along a membrane

18. Postsynaptic potentials • The membranes of dendrites and cell bodies do not have action potentials. Instead, any depolarizing stimulus causes a post synaptic potential (PSP) which spreads out across the membrane. The depolarization is weaker the further it gets from the stimulus. When the stimulus is turned off, the PSP disappears.

19. Postsynaptic potentials • Postsynaptic potentials can either be excitatory (depolarization) or inhibitory. • Excitatory and inhibitory potentials can summate both in time (temporal summation) and across the membrane (spatial summation) . • The net effect of summation is reflected at the axon hillock where action potentials are generated.

20. The synapse • Normally, cell bodies are stimulated by either by • stimuli in the environment, e.g. sensory cells like the rods and cones in the eye, or • Connections from other nerve cells, i.e., synapses

21. The Synapse

22. The Synapse

23. Synapse Any neuron can have thousands of synapses on it

24. Synapse • When an action potential arrives at the terminal bouton, it causes Ca++ channels to open. • This causes the vesicles to move to the membrane and release a chemical called a neurotransmitter to be released into the synaptic cleft. • The neurotransmitter diffuses across the cleft and activates receptors on the postsynaptic membrane which cause changes on the resting potential by altering the functioning of ion channels.

25. Proteins • Ion pumps, ion channels, etc., are large molecules of protein. • Proteins are long strings of amino acids that can fold into many three dimensional shapes. The same protein can have different configurations, i.e., they can change shape. • Receptors are protein molecules that change shape (are activated) by neurotransmitter molecules with a particular shape.

26. Receptors • Receptor sites can be part of an ion channel and when the receptor site is occupied by a neurotransmitter, the ion channel opens

27. Post synaptic potential • The change in the resting potential caused by the activation of a receptor site is called the post synaptic potential (PSP). • IPSP – when the change causes hyperpolarization or makes the cell harder to fire, this is called an inhibitory post synaptic potential. • EPSP – when the change causes depolarization, this is called an excitatory post synaptic potential.

28. Post synaptic potential The excitation and inhibition caused by all the active synapses on the dendrites and cell body are summed and the net effect is reflected in the rate at which the axon hillock generates action potentials

29. Summation

30. Terminating synaptic action • Once the neurotransmitter is released into the cleft, there must be a means by which its activity is terminated. This can be accomplished two ways • The neurotransmitter can be destroyed by an enzyme in the cleft • The neurotransmitter can be reabsorbed back into the bouton (reuptake).

31. Second messenger The neurotransmitter causes the release of a molecule inside the cell which activates an ion channel and causes it to open

32. Second messenger cascade

33. Second messenger cascade • Second messenger molecules can activate a kinase which lasts for minutes and hours. • Kinases can activate transcription factors (CREB and c-fos) which alter the expression of genes. • Genes carry the codes for the creation of proteins including ion channels and receptor sites and this can cause permanent changes in synaptic function.

34. autoreceptors • The membrane of the presynaptic cell has many receptor sites which detect the neurotransmitter. This is a feedback system which regulated the amount of neurotransmitter released into the cleft

35. Other signaling between neurons Neuromodulators are chemicals that can alter the effect of a neurotransmitter. Sometimes the postsynaptic membrane releases molecules that affect the presynaptic membrane. DSE- depolarization-induced suppression of excitation DSI – depolarization-induced suppression of inhibition. Axo-axonal synapses: axons may also have synapses

36. Neurotransmitters Acetylcholine (Ach) Biogenic amines (monoamines) catecholamines: Norepinephrine (NE) Dopamine (DA) Epinephrine (E) (adrenaline) indoleamine Serotonin (5-HT, 5-hydroxytryptamine)

37. Amino acids: GABA Glycine Glutamate Proline

38. Peptides Substance P Somatostatin Vasopressin Growth hormone Prolactin Insulin Opiate-like transmitters Enkephalins Endorphins

39. carbon monoxide nitric oxide

40. Many hormones are neurotransmitters. Both have the same function: chemical signalling over distances.

41. Neurohormones Substances that act at neuron receptor sites, but are not specific to an individual synapse. May be released far from the synapse. Act as a neuromodulator (modify the activity of a neurotransmitter)

42. Dale’s Law A single neuron always produces the same transmitter at every one of its synapses. It is now known that the law is not always right.

43. Drugs mostly act on the nervous system by interacting with neurotransmission, They may: act on receptor sites and cause the same effect as a transmitter: agonism block a receptor site: antagonism decreasing activity of enzymes that destroy a transmitter block reuptake mechanisms blocking ion channels altering release of transmitter altering the action of neurohormones

44. Synapses that use NE are nor adrenergic (remember, adrenaline is another word for epinephrine) DA are dopaminergic 5-HT are serotonergic ACh are cholinergic etc

45. Acetylcholine: Broken down by AchE (acetylcholinesterase) Receptors: nicotinic and muscarinic Stimulated Blocked Function nicotinic nicotine curare Voluntary muscle control (neuromuscular junctions) muscarinic muscarine atropine Involuntary muscle control botox and nerve gasses

46. Biogenic amines Serotonin, Dopamine Norepinephrine and Epinephrine Broken down by MAO and COMT Reabsorbed by transporter mechanisms Influenced by amphetamines and cocaine and SSRIs and SNRIs E and NE receptor sites alpha (α)and Beta (β) with subtypes 1 and 2 DA has 6 receptor subtypes D1 and D2....D6 with sub sub types a b c, etc Serotonin has 4 main receptor subtypes with sub sub types a b c etc.

47. GABA • Universally inhibitory transmitter • Opens a Chloride ion channel which stabilizes the membrane and makes it harder to depolarize • Drugs like benzodiazepines enhance the ability of GABA to open the ion channel. • There are two types of GABA receptors; GABAA and GABAB. • There are many different subtypes of GABAA receptors which control different functions. • GABAB receptors are less common and use a second messenger

48. GABA

49. Glutamate excitatory transmitter NMDA receptor open ion channel and lets +ions into the cell the channels can be blocked by alcohol, solvents and some hallucinogens Peptides opioid type peptides enkephalins (5 amino acids) endorphines (16 to 30 amino acids) Receptor subtypes mu, kappa and delta

50. The Nervous System Central Nervous System (CNS) brain and spinal cord Peripheral Nervous system (PNS) everything else