2. Section 2: Signal Transmission Between the Neurons

3. Neurotransmission 1.Chemical synapse (Classical Synapse) –Predominates in the vertebrate nervous system 2.Non-synaptic chemical transmission 3.Electrical synapse –Via specialized gap junctions –Does occur, but rare in vertebrate NS –Astrocytes can communicate via gap junctions

4. Chemical Synapse Terminal bouton is separated from postsynaptic cell by synaptic cleft. Vesicles fuse with axon membrane and NT released by exocytosis. Amount of NTs released depends upon frequency of AP.

5. Non-synaptic chemical transmission The postganglionic neurons innervate the smooth muscles.  No recognizable endplates or other postsynaptic specializations;  The multiple branches are beaded with enlargements (varicosities) that are not covered by Schwann cells and contain synaptic vesicles; Fig. : Ending of postganglionic autonomic neurons on smooth muscle

6.  In noradrenergic neurons, the varicosities are about 5  m, with up to 20,000 varicosities per neuron;  Transmitter is apparently released at each varicosity, at many locations along each axon;  One neuron innervate many effector cells. Fig. : Ending of postganglionic autonomic neurons on smooth muscle Non-synaptic chemical transmission continued

7. Electrical Synapse Impulses can be regenerated without interruption in adjacent cells. Gap junctions: –Adjacent cells electrically coupled through a channel. –Each gap junction is composed of 12 connexin proteins. Examples: –Smooth and cardiac muscles, brain, and glial cells.

8. Electric current flow- communication takes place by flow of electric current directly from one neuron to the other No synaptic cleft or vesicles cell membranes in direct contact Communication not polarized- electric current can flow between cells in either direction Electrical Synapses

9. Electrical Synapse Chemical Synapse Purves, 2001

10. I The Chemical Synapse and Signal Transmission

11. The chemical synapse is a specialized junction that transfers nerve impulse information from a pre synaptic membrane to a postsynaptic membrane using neurotransmitters and enzymes

12. Synaptic connections ~100,000,000,000 neurons in human brain Each neuron contacts ~1000 cells Forms ~10,000 connections/cell How many synapses?

13. Neurotransmitter- communication via a chemical intermediary called a neurotransmitter, released from one neuron and influences another Synaptic cleft- a small gap between the sending (presynaptic) and the receiving (postsynaptic) site Chemical Synapses

14. Synaptic vesicles- small spherical or oval organelles contain chemical transmitter used in transmission Polarization- communication occurs in only one direction, from sending presynaptic site, to receiving postsynaptic site Chemical Synapses

15. Precursor transport NT synthesis Storage Release Activation Termination ~diffusion, degradation, uptake, autoreceptors 1. Synaptic Transmission Model

16. Presynaptic Axon Terminal Postsynaptic Membrane Terminal Button Dendritic Spine

17. (1) Precursor Transport

18. ______ NT (2) Synthesis enzymes/cofactors

19. (3) Storage in vesicles

20. Synapse Vesicles NT Terminal Button Dendritic Spine

21. Synapse Terminal Button Dendritic Spine (4) Release Receptors

22. Synapse Terminal Button Dendritic Spine AP

23. Ca 2+ Exocytosis

24. Each vesicle contains one quanta of neurotransmitter (approximately 5000 molecules) – quanta release

25. (5) Activation

26. (6) Termination

27. (6.1) Termination by... Diffusion

28. (6.2) Termination by... Enzymatic degradation

29. (6.3) Termination by... Reuptake

30. (6.4) Termination by... Autoreceptors A

31. On presynaptic terminal Binds NT same as postsynaptic receptors different receptor subtype Decreases NT release & synthesis Metabotropic receptors

32. Synaptic Transmission AP travels down axon to bouton. VG Ca 2+ channels open. –Ca 2+ enters bouton down concentration gradient. –Inward diffusion triggers rapid fusion of synaptic vesicles and release of NTs. Ca 2+ activates calmodulin, which activates protein kinase. Protein kinase phosphorylates synapsins. –Synapsins aid in the fusion of synaptic vesicles.

33. Synaptic Transmission (continued) NTs are released and diffuse across synaptic cleft. NT (ligand) binds to specific receptor proteins in postsynaptic cell membrane. Chemically-regulated gated ion channels open. –EPSP: depolarization. –IPSP: hyperpolarization. Neurotransmitter inactivated to end transmission.

34. 2 EPSP and IPSP

35. (1)Excitatory postsynaptic potential (EPSP)  An AP arriving in the presynaptic terminal cause the release of neurotransmitter;  The molecules bind and active receptor on the postsynaptic membrane;

36. (1)Excitatory postsynaptic potential (EPSP)  Opening transmitter- gated ions channels ( Na + ) in postsynaptic- membrane;  Both an electrical and a concentration gradient driving Na + into the cell;  The postsynaptic membrane will become depolarized(EPSP).

37. EPSP No threshold. Decreases resting membrane potential. –Closer to threshold. Graded in magnitude. Have no refractory period. Can summate.

38. (2) Inhibitory postsynaptic potential (IPSP) A impulse arriving in the presynaptic terminal causes the release of neurotransmitter; The molecular bind and active receptors on the postsynaptic membrane open CI - or, sometimes K + channels; More CI - enters, K + outer the cell, producing a hyperpolarization in the postsynaptic membrane.

39. (IPSPs): –No threshold. –Hyperpolarize postsynaptic membrane. –Increase membrane potential. –Can summate. –No refractory period.

41. 3 Synaptic Inhibition Presynaptic inhibition: –Amount of excitatory NT released is decreased by effects of second neuron, whose axon makes synapses with first neuron’s axon. Postsynaptic inhibition

42.  Concept: effect of inhibitory synapses on the postsynaptic membrane.  Mechanism: IPSP, inhibitory interneuron  Types:  Afferent collateral inhibition( reciprocal inhibition)  Recurrent inhibition. (1) Postsynaptic inhibition

43. 1) Reciprocal inhibition Activity in the afferent fibers from the muscle spindles (stretch receptors) excites (EPSPs) directly the motor neurons supplying the muscle from which the impulses come. Postsynaptic inhibition At the same time, inhibits (ISPSs) those motor neurons supplying its antagonistic muscles.

44. 1) Reciprocal inhibition The latter response is mediated by branches of the afferent fibers that end on the interneurons. Postsynaptic inhibition The interneurons, in turn, secrete the inhibitory transmitter (IPSP) at synapses on the proximal dendrites or cell bodies of the motor neurons that supply the antagonist.

45. Neurons may also inhibit themselves in a negative feedback fashion. Each spinal motor neuron regularly gives off a recurrent collateral that synapses with an inhibitory interneuron which terminates on the cell body of the spinal neuron and other spinal motor neurons. The inhibitory interneuron to secrete inhibitory mediator, slows and stops the discharge of the motor neuron. 2) Recurrent inhibition Postsynaptic inhibition

46. Concept: the inhibition occurs at the presynaptic terminals before the signal ever reaches the synapse. The basic structure: an axon-axon synapse (presynaptic synapse), A and B. Neuron A has no direct effect on neuron C, but it exert a Presynaptic effect on ability of B to Influence C. The presynatic effect May decrease the amount of neuro- transmitter released from B (Presynaptic inhibition) or increase it (presynaptic facilitation). (2) Presynaptic inhibition A A B C A C B

47. The mechanisms: Activation of the presynaptic receptors increases CI - conductance,  to decrease the size of the AP reaching the excitatory ending,  reduces Ca 2+ entry and consequently the amount of excitatory transmitter decreased. Presynaptic inhibition Voltage-gated K+ channels are also opened, and the resulting K+ efflux also decreases the Ca2+ influx.

48. Excitatory Synapse A active B more likely to fire Add a 3d neuron ~ A B + Presynaptic Inhibition

49. Excitatory Synapse Axon-axon synapse C is inhibitory ~ A B + Presynaptic Inhibition C -

50. Excitatory Synapse A B + Presynaptic Inhibition C - C active less NT from A when active B less likely to fire ~

51. 4 Synaptic Facilitation: Presynaptic and Postsynaptic

52. Excitatory Synapse A active B more likely to fire ~ A B + (1) Presynaptic Facilitation

53. Excitatory Synapse A B + Presynaptic Facilitation C + C active (excitatory) more NT from A when active (Mechanism: AP of A is prolonged and Ca 2+ channels are open for a longer period.) B more likely to fire ~

54. (2) Postsynaptic facilitation: neuron that has been partially depolarized is more likely to undergo AP.

55. -65mv - 70mvAT REST VmVm Time EPSP + - Depolarization more likely to fire ~ Record here +

56. 5 Synaptic Integration EPSPs can summate, producing AP. –Spatial summation: Numerous PSP converge on a single postsynaptic neuron (distance). –Temporal summation: Successive waves of neurotransmitter release (time).

57. (1) Spatial Summation The accumulation of neurotransmitter in the synapse due the combined activity of several presynaptic neurons entering the Area (Space) of a Convergent Synapse. A space (spatial) dependent process.

58. -65mv - 70mvAT REST vmvm Time + - Spatial Summation + Multiple synapses +

59. (2) Temporal Summation The accumulation of neurotransmitters in a synapse due to the rapid activity of a presynaptic neuron over a given Time period. Occurs in a Divergent Synapse. (explain later) Is a Time (Temporal) dependent process.

60. -65mv - 70mvAT REST VmVm Time + - Temporal Summation + n Repeated stimulation n same synapse ~

61. (3) EPSPs & IPSPs summate CANCEL EACH OTHER Net stimulation –EPSPs + IPSPs = net effects ~

62. - 70mv + - - EPSP IPSP +

63. 6. Divergent and Convergent Synapse

64. Divergent Synapse A junction that occurs between a presynaptic neuron and two or more postsynaptic neurons (ratio of pre to post is less than one). The stimulation of the postsynaptic neurons depends on temporal summation).

65. Convergent Synapse Presynaptic neurons Postsynaptic neuron A junction between two or more presynaptic neurons with a postsynaptic neuron (the ratio of pre to post is greater than one). The stimulation of the postsynaptic neuron depends on the Spatial Summation.

66. II Neurotransmitters and receptors

67. 1. Basic Concepts of NT and receptor Neurotransmitter: Endogenous signaling molecules that alter the behaviour of neurons or effector cells. Neuroreceptor: Proteins on the cell membrane or in the cytoplasm that could bind with specific neurotransmitters and alter the behavior of neurons of effector cells

68. Vast array of molecules serve as neurotransmitters The properties of the transmitter do not determine its effects on the postsynaptic cells The properties of the receptor determine whether a transmitter is excitatory or inhibitory

69. A neurotransmitter must (classical definition) Be synthesized and released from neurons Be found at the presynaptic terminal Have same effect on target cell when applied externally Be blocked by same drugs that block synaptic transmission Be removed in a specific way Purves, 2001

70. Classical Transmitters (small-molecule transmitters) Biogenic Amines Acetylcholine Catecholamines Dopamine Norepinerphrine Epinephrine Serotonin Amino Acids Glutamate GABA (  -amino butyric acid) Glycine Neuropeptides Neurotrophins Gaseous messengers –Nitric oxide –Carbon Monoxide D-serine Non-classical Transmitters

71. Agonist A substance that mimics a specific neurotransmitter, is able to attach to that neurotransmitter's receptor and thereby produces the same action that the neurotransmitter usually produces. Drugs are often designed as receptor agonists to treat a variety of diseases and disorders when the original chemical substance is missing or depleted.

72. Antagonist Drugs that bind to but do not activate neuroreceptors, thereby blocking the actions of neurotransmitters or the neuroreceptor agonists.

73. Receptor B Receptor A Same NT can bind to different -R different part of NT ~ NT

74. Specificity of drugs Drug A Drug B Receptor B Receptor A

75. Five key steps in neurotransmission Synthesis Storage Release Receptor Binding Inactivation Purves, 2001

76. Synaptic vesicles Concentrate and protect transmitter Can be docked at active zone Differ for classical transmitters (small, clear-core) vs. neuropeptides (large, dense-core)

77. Neurotransmitter Co-existence (Dale principle) Some neurons in both the PNS and CNS produce both a classical neurotransmitter (ACh or a catecholamine) and a polypeptide neurotransmitter. They are contained in different synaptic vesicles that can be distinguished using the electron microscope. The neuron can thus release either the classical neurotransmitter or the polypeptide neurotransmitter under different conditions.

78. Purves, 2001

79. Receptors determine whether: Synapse is excitatory or inhibitory –NE is excitatory at some synapses, inhibitory at others Transmitter binding activates ion channel directly or indirectly. –Directly ionotropic receptors fast –Indirectly metabotropic receptors G-protein coupled slow

80. 2. Receptor Activation Ionotropic channel –directly controls channel –fast Metabotropic channel –second messenger systems –receptor indirectly controls channel ~

81. (1) Ionotropic Channels neurotransmitter NT Channel

82. Ionotropic Channels NT Pore

83. Ionotropic Channels NT

84. Ionotropic Channels NT

85. (2) Metabotropic Channels Receptor separate from channel G proteins 2d messenger system –cAMP –other types Effects –Control channel –Alter properties of receptors –regulation of gene expression ~

86. (2.1) G protein: direct control NT is 1st messenger G protein binds to channel –opens or closes –relatively fast ~

87. G protein: direct control R G GDP

88. G protein: direct control R G GTP Pore

89. (2.2) G protein: Protein Phosphorylation Receptor trans- ducer primary effector external signal: nt 2d messenger secondary effector Receptor trans- ducer primary effector external signal: NT 2d messenger secondary effector GSGS norepinephrine cAMP protein kinase  adrenergic -R adenylyl cyclase

90. G protein: Protein Phosphorylation R G GDP ACAC PK

91. G protein: Protein Phosphorylation R ACAC PK G GTP ATP cAMP

92. G protein: Protein Phosphorylation R ACAC PK G GTP ATP cAMP P Pore

93. (3) Transmitter Inactivation Reuptake by presynaptic terminal Uptake by glial cells Enzymatic degradation Presynaptic receptor Diffusion Combination of above

94. Summary of Synaptic Transmission Purves,2001

95. Basic Neurochemistry

96. 3. Some Important Transmitters

97. (1) Acetylcholine (ACh) as NT

98. Acetylcholine Synthesis choline+ acetyl CoA ACh + CoA choline acetyltransferase

99. Acetylcholinesterase (AChE) Enzyme that inactivates ACh. –Present on postsynaptic membrane or immediately outside the membrane. Prevents continued stimulation.

101. The Life Cycle of Ach

102. Ach - Distribution Peripheral N.S. Excites somatic skeletal muscle (neuro-muscular junction) Autonomic NS Ganglia Parasympathetic NS--- Neuroeffector junction Few sympathetic NS – Neuroeffector junction Central N.S. - widespread Hippocampus Hypothalamus ~

103. ACh is both an excitatory and inhibitory NT, depending on organ involved. –Causes the opening of chemical gated ion channels. Nicotinic ACh receptors: –Found in autonomic ganglia (N 1 ) and skeletal muscle fibers (N 2 ). Muscarinic ACh receptors: –Found in the plasma membrane of smooth and cardiac muscle cells, and in cells of particular glands. Ach Receptors

104. Acetylcholine Neurotransmission “Nicotinic” subtype Receptor: –Membrane Channel for Na + and K + –Opens on ligand binding –Depolarization of target (neuron, muscle) –Stimulated by Nicotine, etc. –Blocked by Curare, etc. –Motor endplate (somatic) (N 2 ), –all autonomic ganglia, hormone producing cells of adrenal medulla (N 1 )

105. Acetylcholine Neurotransmission “Muscarinic” subtype Receptor: M 1 –Use of signal transduction system Phospholipase C, IP 3, DAG, cytosolic Ca ++ –Effect on target: cell specific (heart , smooth muscle intestine  ) –Blocked by Atropine, etc. –All parasympathetic target organs –Some sympathetic targets (endocrine sweat glands, skeletal muscle blood vessels - dilation)

106. Acetylcholine Neurotransmission “Muscarinic” subtype: M 2 –Use of signal transduction system via G-proteins, opens K + channels, decrease in cAMP levels –Effect on target: cell specific –CNS –Stimulated by ? –Blocked by Atropine, etc.

107. Cholinergic Agonists Direct –Muscarine –Nicotine Indirect –AChE Inhibitors ~

108. Cholinergic Antagonists Direct Nicotinic - Curare Muscarinic - Atropine

109. Ligand-Operated ACh Channels N Receptor

110. G Protein-Operated ACh Channel M receptor

111. (2) Monoamines as NT

112. Monoamines Catecholamines – Dopamine - DA Norepinephrine - NE Epinephrine - E Indolamines - Serotonin - 5-HT

113. Mechanism of Action (  receptor)

114. Epi 11 G protein PLC IP 3 Ca +2

115. Norepinephrine (NE) as NT NT in both PNS and CNS. PNS: –Smooth muscles, cardiac muscle and glands. Increase in blood pressure, constriction of arteries. CNS: –General behavior.

117. Adrenergic Neurotransmission  1 Receptor –Stimulated by NE, E, –blood vessels of skin, mucosa, abdominal viscera, kidneys, salivary glands –vasoconstriction, sphincter constriction, pupil dilation

118. Adrenergic Neurotransmission  2 Receptor –stimulated by, NE, E, ….. –Membrane of adrenergic axon terminals (pre- synaptic receptors), platelets –inhibition of NE release (autoreceptor), –promotes blood clotting, pancreas decreased insulin secretion

119. Adrenergic Neurotransmission  1 receptor –stimulated by E, …. –Mainly heart muscle cells, –increased heart rate and strength

120. Adrenergic Neurotransmission  2 receptor –stimulated by E.. –Lungs, most other sympathetic organs, blood vessels serving the heart (coronary vessels), – dilation of bronchioles & blood vessels (coronary vessels), relaxation of smooth muscle in GI tract and pregnant uterus

121. Adrenergic Neurotransmission  3 receptor –stimulated by E, …. –Adipose tissue, –stimulation of lipolysis

122. (3) Amino Acids as NT Glutamate acid and aspartate acid: –Excitatory Amino Acid (EAA) gamma-amino-butyric acid (GABA) and glycine: –Inhibitory AA

123. (4) Polypeptides as NT CCK: –Promote satiety following meals. Substance P: –Major NT in sensations of pain.

124. (5) Monoxide Gas: NO and CO Nitric Oxide (NO) –Exerts its effects by stimulation of cGMP. –Involved in memory and learning. –Smooth muscle relaxation. Carbon monoxide (CO): –Stimulate production of cGMP within neurons. –Promotes odor adaptation in olfactory neurons. –May be involved in neuroendocrine regulation in hypothalamus.