1. Synapses and Synaptic Transmission
Dr. Donald Allen

2. Learning Objectives Describe the basic features of a synapse.
Describe the events that occur at a synapse from the time an action potential reaches the synapse to the time when the neurotransmitter is released.
Describe the electrical changes that occur at the postsynaptic terminal.
Describe the mechanism for presynaptic facilitation and presynaptic inhibition.
Explain the differences between ligand-gated ion channels and G-protein mediated receptors.

3. Identify the major second messenger systems in the nervous system.
Identify the major neurotransmitter systems in the nervous system and their major functions.
Identify the primary excitatory and inhibitory neurotransmitters in the brain and spinal cord.
Describe the stages that occur in the life of a neurotransmitter molecule, (including storage in vesicles, release into the synaptic cleft, binding to receptors and either degradation or reuptake by the presynaptic terminal) and identify drugs that may interfere at these stages.
Describe the mechanism and role of receptor regulation
Describe the pathology of Lambert-Eaton syndrome and Myasthenia Gravis.

4. What are synapses?
What is their function?

5. Main Components of a Synapse
Presynaptic terminal
Postsynaptic terminal
Synaptic cleft
Vesicles
Neurotransmitters

6. Where are Synapses located?
A synapse is between the axon of the presynaptic neuron and a region of the postsynaptic cell.
Where do we see synapses on the postsynaptic cell?
Do synapses with different locations have different functions?

7. Axo-

8. How Synapses Function Action potential reaches presynaptic terminal
Calcium enters presynaptic terminal
Voltage-gated calcium ion channels
Vesicles move toward release site
Presynaptic terminal releases neurotransmitter
Neurotransmitter binds to postsynaptic receptors
Membrane channel changes configuration and ions enter postsynaptic cell
Can also activate intracellular messengers

9. What determines how much neurotransmitter is released?

10. Electrical Potentials at the Synapse
Neurotransmitter binding to receptors can open ion channels
At the neuromuscular junction or at axosomatic and axodendritic synapses, ion channel opening can generate a local postsynaptic potential
The potentials can be depolarizing or hyperpolarizing

11. Postsynaptic potentials
Excitatory postsynaptic potential – EPSP
De- or hyper-polarization
Nicotinic ACh receptor – _____________
_____________ channels
Inhibitory postsynaptic potential – IPSP
_____________ ion channels

12. Actions of EPSPs In nervous system At neuromuscular junction
EPSPs can summate to generate an action potential
_____________
At neuromuscular junction
Each action potential in motor neuron produces a sufficient EPSP in muscle that there is muscle contraction

13. Actions of IPSPs
IPSPs can inhibit the generation of an action potential
What happens when there are both EPSPs and IPSPs at a postsynaptic neuron

14. Presynaptic Facilitation
Where are the synapses
Axo-
Depolarization –
Makes an action potential last ________ at the second axon presynaptic terminal
The number of calcium ions that enter the presynaptic terminal is _____________

15. Presynaptic Facilitation
The change in calcium ions causes more vesicles to release their neurotransmitter

16. Presynaptic Inhibition
Hyperpolarization –
Makes an action potential last ________ at the second axon presynaptic terminal
The number of calcium ions that enter the presynaptic terminal is _____________
The change in calcium ions causes less vesicles to release their neurotransmitter

17. Neurotransmitters and Neuromodulators
Excite or inhibit postsynaptic neuron
Effect lasts less than 1/10th of a second
Neuromodulator
Effect G-proteins which activate second messengers
Longer lasting (minutes to days)

18. Functional and Anatomical Organization of Neurochemical Systems
Local circuits
Diffuse systems
Relay systems

19. Classification of Neurotransmitters and Neuromodulators
Acetylcholine
Amino acids
Monoamines
Peptides
Other

20. Acetylcholine Cholinergic systems Receptors N M Amanita muscaria

21. Acetylcholine Metabolism
Acetyl-Coenzyme A and Choline
Choline acetyltransferase (CAT)
Acetylcholine
Acetylcholinesterase (AChE)
Acetate and Choline

22. Peripheral ACh Neuromuscular junction Autonomic nervous system
Receptor:
Function:
Autonomic nervous system
Receptors:

23. Central ACh Receptors Function Both nicotinic and muscarinic
Autonomic regulation
Selection of objects of attention

24. Amino Acids Main neurotransmitters of central nervous system
Excitatory amino acids
Aspartate
Glutamate
Inhibitory amino acids
Glycine
Gamma-aminobutyric acid (GABA)

25. Glutamate Principal fast neurotransmitter Functions Learning
Development
Neuronal death after CNS injury

26. Inhibitory Amino Acids

27. Both act to prevent excessive neural activity
Glycine
Inhibits postsynaptic membranes, particularly in brainstem and spinal cord
GABA
Major inhibitory neurotransmitter in CNS
Interneurons in spinal cord
Receptors: GABAA and GABAB
Both act to prevent excessive neural activity
Blocking the effects of these neurotransmitters can produce seizures

28. Monoamines Moderate sized group Cell bodies of these neurons?
Norepinephrine (noradrenaline)
Dopamine
Serotonin
Histamine
Cell bodies of these neurons?
Overall functions?

29. Catecholamines: Dopamine and Norepinephrine
Phenylalanine
Tyrosine
Dihydroxyphenyl-alanine (l-DOPA)
Dopamine

30. Further metabolism of catecholamines
Dopamine
Norepinephrine
Epinephrine

31. Structure of some catecholamines

32. Dopamine Motor activity (Parkinson’s Disease)
l-DOPA
Cognition (Schizophrenia)
Dopamine receptor blockers
Motivation
Addiction
Cocaine
Amphetamine

33. Norepinephrine Autonomic nervous system Attention and Vigilance
Fight or fight response
Panic disorder
Attention and Vigilance

34. Serotonin
AKA 5-hydroxytryptamine

35. Serotonin functions Regulation of blood vessels
Low levels of serotonin associated with depression and suicide
SSRI – selective serotonin reuptake inhibitors
Fluoxetine (Prozac)
Sleep

36. Histamine Concentrated in hypothalamus
Helps regulate hormonal function

37. Peptides Very broad category Many different functions
More modulators than neurotransmitters
There are several families of peptides

38. Peptide release
Many neurons contain both a peptide neuromodulator and a more traditional neurotransmitter
With low stimulation, usually the neuron releases just the neurotransmitter
With high levels of stimulation, both the peptide and the neurotransmitter are released

39. Endogenous opioid peptides
Bind to the same receptors that opiate drugs bind to
Three families
Endorphins
Enkephalins
Dynorphins
Each family comes from a different gene

40. In general, involved in pain inhibition
Endorphins and enkephalins involved in ‘runner’s high’
Also important in regulation of hormonal systems

41. Substance P P is for pain
Substance P acts as a neurotransmitter in some of the neurons in the sensory pathways that relay pain sensation

42. Other peptides ACTH (pituitary) Vasopressin (pituitary) Neurotensin
Cholecystokinin
Somatostatin (hypothalamus)

43. Miscellaneous Neurotransmitters
Nitrous oxide
Neuromodulator
Regulates vascular systems
Cell death of neurons
Changes in postsynaptic neuron in response to repeated stimuli
Carbon monoxide
Short-lasting, rapid effects
Affects neurotransmitter release

44. Receptors
Most neurotransmitters and neuromodulators act by binding to specific proteins on the postsynaptic membrane termed receptors
Substances which bind to receptors are called ligands
Most receptors named after the ligand that binds to them
Some important exceptions

45. Types of Receptors Ligand-gated ion channels
G-protein mediated receptors

46. Ligand-gated ion channels
Receptor and ion channel are the same complex
Actions usually rapid and brief
Mechanism
Ligand binds to receptor
Ion channel opens
Ions travel through channel
Local membrane depolarization or hyperpolarization

47. Nicotinic Acetylcholine Receptor
Located at neuromuscular junction
Best studied receptor
Made up of 5 subunits

48. Nicotinic AChR Two molecules of ACh bind to the receptor
Ion channel opens
Permeable to both Na+ and K+
Overall effect is depolarization
More Na+ enters than K+ leaves the muscle fiber
Channel open for only a few milliseconds

49. Action at the receptor ends when:
Neurotransmitter diffuses away from the synaptic cleft
Neurotransmitter is broken down into an inactive form
Acetylcholinesterase (ACh)
Monoamine oxidase (monoamines)
Peptidases (peptide neuromodulators)
Neurotransmitter is taken up into the presynaptic terminal

50. G-protein mediated receptors
AKA: 7-transmembrane receptor
Picture next slide
Effects slower and longer lasting
Open/close ion channel
Activate/inhibit enzymes
Regulate calcium levels in cell
Activate/inactivate genes

51. Beta-2 adrenergic receptor

52. Mechanism of Action Can be stimulatory, inhibitory or modulatory
Involve activation/inhibition of second messenger systems
Note that this can give us amplification of the ligand. One ligand-activated receptor can produce multiple 2nd messengers. If the 2nd messengers activate enzymes, we have a further magnification of the response

53. Second messengers Cyclic AMP (cAMP)
Modulates ion channels (pain sensation in PNS)
Activates cAMP dependent proteins/enzymes
Arachidonic acid – derived from lipids
Produces prostaglandins – aspirin blocks PG synthesis
regulate vasodilation
Enhances inflammation
Inositol triphosphate
Regulates Calcium ion stores

54. G-protein action cAMP as 2nd Messenger

55. G-protein action Phosphoinositol as 2nd Messenger

56. Types of Receptors Acetylcholine Aminoacid Norepinephrine Dopamine
Serotonin
Opioid peptide

57. Acetylcholine Receptors
Nicotinic – ligand-gated ion channel
Neuromuscular junction
Autonomic ganglia
Some parts of CNS
Functions
Memory and learning
Alzheimer’s disease
Neuronal development

58. Muscarinic Acetylcholine Receptors
G-protein linked receptors
Autonomic targets – heart
Selected areas of brain
Autonomic function – Parasympathetic
Slow heart

59. Glutamate Receptors Both ion channels and G-protein linked
Ion Channels – named for drugs that bind
AMPA – fast acting
Kainate – fast acting
NMDA – slow opening and closing of ion channels
G-protein – metabotropic receptors

60. NMDA receptors Function Normal neurotransmission
Long-term changes in the CNS
Long-term potentiation (next section)
Learning and memory

61. NMDA receptors and pathology
Neuronal cell death
Injury to part of the brain can produce cell death in surrounding regions
Overactivity may cause epileptic seizures
Phencylclidine (PCP, angel dust) acts on NMDA receptors
Other pathologies
Acute stroke, chronic pain, Parkinson’s disease, schizophrenia

62. GABA receptors GABA-A receptors Chloride ion-channel linked
Effect on cell membrane?
Barbiturates bind
Sedation
Decrease anxiety (anxiolytic)
Anticonvulsants for treating seizures

63. Baclofen – muscle relaxant All GABA receptors tend to be inhibitory
GABA-B receptors
G-protein mediated
Linked to ion channels through 2nd messengers
Baclofen – muscle relaxant
All GABA receptors tend to be inhibitory

64. Dopamine Receptors Dopaminergic receptors 5 types – D1, D2, D3, D4, D5
Main types
D1, also D3, D5
D2, also D4
D1 and D2 can have the opposite effects

65. Norepinephrine receptors
Alpha-receptors (alpha-1 and alpha-2)
Beta-receptors (beta-1 and beta-2)
Beta-1
Heart: increase force and rate of contraction
Beta-blockers
Beta-2
Lungs: bronchodilation
Inhalers for asthma

66. Serotonin receptors 5-HT receptors Cognition Sleep
Multiple types
Cognition
Sleep
Perception (including pain)
Motor activity
Mood

67. Opioid peptide receptors
Several types Mu
Delta
Kappa
Primary action is inhibition of slow pain information
Location: hypothalamus, spinal cord, and periaqueductal gray

68. How can we change synaptic transmission?
Drugs can interfere at many different stages
Synthesis of neurotransmitter
Packaging in vesicles
Regulating calcium ions in presynaptic terminal
Release of neurotransmitter from vesicles
Binding of neurotransmitter to receptors
Degradation of neurotransmitter
Re-uptake of neurotransmitter

69. Synthesis of Neurotransmitter
l-DOPA

70. Packaging in vesicles
Reserpine

71. Calcium Ion regulation
Lambert-Eaton syndrome

72. Neurotransmitter release
Botulinum toxin poisoning
Blocks release of ACh at the neuromuscular junction
Used to treat (short-term) spasticity
Used for cosmetic reasons

73. Receptor binding
Agonists
Antagonists
Myasthenia gravis

74. Neurotransmitter Degradation
Monoamine oxidase inhibitors (MAO-I)
Acetylcholinesterase inhibitors

75. Neurotransmitter Reuptake
Tricyclic antidepressants
Inhibit monoamine reuptake
Tend to act at cholinergic receptors also
Selective serotonin reuptake inhibitors
Prozac (serotonin)

76. Lambert-Eaton Syndrome
Mostly seen in patients with cancer, usually small cell carcinoma of the lung
Antibodies are produced against voltage-gated calcium channel of the neuromuscular junction
Antibodies block calcium entry into presynaptic terminal
What affect will this have on ACh release and muscle strength?

77. Myasthenia gravis Antibodies to the nicotinic acetylcholine receptor
Antibody blocks the effect of ACh on the muscle
Increasing weakness seen with repeated use of a muscle
Initial sign in about 50% of patients
Weakness opening eyelids or moving eyes. Why?

78. Other muscles commonly affected
Facial muscles
Muscles for swallowing
Proximal limb muscles
Respiratory muscles
Demographics of onset
Women: 20-30
Men: 60-70

79. Treatment Acetylcholinesterase inhibitors Removal of thymus gland
Immunosuppressive drugs
Plasmapheresis: removes antibodies

80. Questions before Chapter 4