7_NM3 Synaptic Transmission in physiology

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1. NM3: SYNAPTIC TRANSMISSION 11/22/2019 1

2. Objectives General concept of synaptic transmission Electrical synapse vs. chemical synapse Synaptic integration and modulation Neurotransmitters and their receptors: Classical and non-classical 11/22/2019 2

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4. Introduction Transfer of electrical signals from one cell to another: Nerve to nerve Nerve to muscle Sensory receptors to nerves Nerves to other cells e.g. glia cells Electrical synapse vs. chemical synapse 11/22/2019 4

5. Electrical synapse Aka gap junctions Low resistance pathway for: Current flow Sharing small molecules between the two cells Plaque-like structures with closely apposed cell membranes filled with electron dense material. 11/22/2019 5

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7. Properties Fast (no synaptic delay) Bidirectional L ow pass filters: transmit slow electrical events more readily Demonstrate specificity in gap junction coupling Main function is to synchronize activity. 11/22/2019 7

8. Modulation Properties altered by: Intracellular pH, voltage and calcium G protein coupled receptors Connexins have phosphorylation sites These alter gap junctions functions by: Changing the channel conductance Formation of new gap junctions Removal of existing ones 11/22/2019 8

9. Chemical synapse 11/22/2019 9

10. Chemical synapse Earlier demonstrations by Otto Loewi in frog’s heart and vagus nerve Typically: Axodendritic / axosomatic Others: Axoaxonic , dendrodendritic , dendrosomatic A synapse could be: mixed synapse, serial synapse, reciprocal synapse and some form a glomerulus 11/22/2019 10

11. Key words Presynaptic terminal Synaptic cleft Neurotransmitters :classical vs. non classical Postsynaptic terminal Metabotropic vs. ionotropic receptors EPSP & IPSP 11/22/2019 11

12. Use the above Key words to summarize Synaptic transmission 11/22/2019 12

13. Transmitter release Calcium entry via voltage gated channels is the trigger Explain the basis of suppression potential? 11/22/2019 13

14. Vesicle hypothesis of NT’s release NT’s are released in a quantal nature EPSP results from summation of the effect of all the NT’s released. The lowest EPSP (mEPP) result from effect of a number of NT’s released from one vesicle. mEPP is the smallest EPP evoked under low calcium levels 11/22/2019 14

15. Vesicular release Docking → Priming → Fusion Involves specialized proteins called SNARE proteins v-SNARE: synaptobrevin t-SNARE: syntaxin & SNAP 25 Involved in docking and priming Targeted by botulinum toxin. Fusion is mediated by a calcium sensor protein called synaptotagmin at the active zone after ↑local calcium levels 11/22/2019 15

16. Recycling of synaptic vesicles 2 mechanisms: Endocytic pathway (fusion & collapse) The kiss & run fusion 11/22/2019 16

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18. Post synaptic potentials EPP EPSP IPSP Safety factor: ratio of synaptic potential to the amplitude needed to reach threshold Higher for muscles than neurons Distinguish fast from slow synaptic transmission 11/22/2019 18

19. The flow of ions across an ion channel is dictated by the electrochemical gradient and predicted by: I x = g x X ( Vm - Ex) The net inward current is called EPSC The potential at which there is no EPSC/EPSP is called the reversal potential. Why does reversal potential occur in ligand gated and not voltage gated channels? 11/22/2019 19

20. EPSP IPSP Depolarizing Depolarizing or hyperpolarizing ↑ probability of an AP ↓ probability of an AP Reversal potential is more positive than threshold: {~0 mV (+/- 10 mV)} Reversal potential is more negative than threshold Main channels: Na+ and K+ Main channels: K+ and Cl - 11/22/2019 20

21. Activity Discuss the differences between an electrical synapse and a chemical synapse. 11/22/2019 21

22. SYNAPTIC INTEGRATION Spatial location in the dendritic tree is an important determinant of efficacy Temporal summation Spatial summation Shunting effect How do IPSPs & EPSPs integrate? 11/22/2019 22

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24. Dendrites and somas of most neurons contain some active elements (gated channels) that can amplify & alter the EPSPs & IPSPs. E.g. Na+ & Ca++ voltage gated channels activated by EPSPs…. Ca++ activated K+ channels…??? Can a hyperpolarizing potential lead to a spike? 11/22/2019 24

25. Modulation of synaptic activity The strength of individual synapses can vary as a function of their use or activity. I’m sure you read in advance, so in appreciation let’s discuss the following: 11/22/2019 25

26. Paired pulse facilitation (PPF) 11/22/2019 26

27. Posttetanic potentiation Mainly due to changes in the presynaptic terminal Increased quanta release of NT’s due to increased intracellular Ca++ from the residual Ca++ from the preceding stimuli 11/22/2019 27

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29. Synaptic depression Presynaptic : depletion of synaptic vesicles Postsynaptic: desensitization of receptors 11/22/2019 29

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31. What happens when potentiation and depression occur in the same synapse? 11/22/2019 31

32. Presynaptic receptors Can modulate neurotransmitter release Presynaptic inhibition Autoreceptors ; serial synapse; nonsynaptically acting NT’s. 11/22/2019 32

33. Activity Discuss long term potentiation and long term depression and the role of calcium and nitric oxide in these and in memory and learning. 11/22/2019 33

34. NEUROTRANSMITTERS 11/22/2019 34

35. Introduction Mediate chemical signaling Criteria: Synthesized by cell and present in presynaptic terminal Released upon depolarization Have receptors on the postsynaptic membrane >100 potential NT’s 11/22/2019 35

36. Classification Small molecule transmitters Acetylcholine Amino acids Biogenic amines Purines Peptides Gaseous transmitters Classical vs. Non classical neurotransmitters 11/22/2019 36

37. A. SMALL MOLECULE TRANSMITTERS ACETYLCHOLINE Location: both CNS & PNS e.g. NMJ Synthesis: acetyl coA + Choline with the aid of cholineacetyltransferase . Fate: Degraded by acetylcholinesterase to acetate & choline (reuptake for recycling) 11/22/2019 37

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39. Receptors: Nicotinic: Ionotropic of cys loop superfamily Pentamers CNS (3 α ,2 β ), NMJ (2 α , β , δ , ε ) EPSP via cation selective channel Muscarinic : Metabotropic via different types of G proteins Subtypes M1-5 11/22/2019 39

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42. 2. Amino acids Glutamate: Excitatory Precursor to GABA Fate??? 11/22/2019 42

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45. b. GABA & Glycine Inhibitory GABA: From glutamate ( glutamic acid decarboxylase ) In spiny neurons of striatum and purkinje of cerebellum Glycine : Generally inhibitory Excitatory at NMDA receptors as a cotransmitter 11/22/2019 45

46. Fate: GABA: uptake to nerve terminals and glia by high affinity Na+- Cl - coupled symporter i.e. GAT1,2,3,4 Glycine : GlyT1&2 which is also a Na+- Cl - coupled symporter . 11/22/2019 46

47. 3. Biogenic amines E, NE, Dopamine, Serotonin, Histamine Fate: Reuptake into glia & neurons via the Na+- Cl - coupled transporter Catecholamines then degraded by MAO & COMT 11/22/2019 47

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50. Location in CNS varies and indicates correlation with their functions. NE- locus ceruleus Serotonin: Raphe nuclei Histamine: tubomammilary nuclei of hypothalamus Dopamine: substantia nigra Epinephrine: autonomic nuclei 11/22/2019 50

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53. 4. Purines ATP: Transmitter or cotransmitter Present in all synaptic vessicles Glia cells may also release ATP Fate: broken down by ATPases and 5’nucleotidases to adenosine (reuptake by presynaptic terminal via adenosine receptors) 11/22/2019 53

54. B. PEPTIDES >100 neuropeptides Main transmitter or co transmitter Compare and contrast the classic and peptide neurotransmitters? 11/22/2019 54

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56. Opioid peptides Opiates vs. opioids 3 major classes: Enkephallins Endorphins Dynorphins Widely distributed in CNS & GIT Analgesics 11/22/2019 56

57. Substance P 11 aa ; in CNS & GIT Pain transmission and affect smooth muscle functions Enkephallins inhibit Sub P at the dorsal root ganglia to inhibit pain pathways 11/22/2019 57

58. C. GAS NEUROTRANSMITTERS Widens scope of synaptic transmission NO, CO No receptors NO: Synthesized upon depolarization by NO synthase As a signal transduction molecule regulating the guanylyl cyclase and acting on vascular smooth muscles 11/22/2019 58

59. RECEPTORS IONOTROPIC: Ligand gated ion channels 4 superfamilies : Cysloop super family (Ach, Serotonin, GABA, Glycine ) Glutamate ATP Transient receptor potential chanels (pain & thermal stimulus) 11/22/2019 59

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61. GABA & Glycine GABA a,c and glycine : Cysloop ionotropic receptors Cl - channels GABA a targeted by Benzodiazepines & Barbiturates GABA b: Metabotropic - GTP – activates K+ chanels and inhibits Ca++ chanels 11/22/2019 61

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63. Glutamate Metabotropic : Grp I (postsynaptic), Grp II,III ( presynaptic ) Ionotropic : AMPA & Kainase Cationic selective chanels Na+, K+, +/- Ca++ NMDA: differs in that it Requires glutamate & glycine to bind to open Display voltage sensitivity due to Mg++ blockade Permeable to calcium & can act as a 2 nd messanger 11/22/2019 63

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65. Purine (ATP) receptors Ionotropic (P2x): cation sensitive (Na+, K+,Ca +) Metabotropic (P2y): G coupled to activate K+ chanells & modulate both NMDA & voltage gated Ca++ chanells Adenosine receptors: Presynaptic Inhibits synaptic transmission by inhibiting Ca++ influx 11/22/2019 65

66. Biogenic amines receptors All metabotropic type receptors except one class of serotonin receptors (5HT3) which are part of the cysloop ionotropic family 11/22/2019 66

67. Neuropeptide receptors All metabotropic like biogenic amines Are exposed to lower agonists concentration More sensitive to their agonists 11/22/2019 67

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69. Gas neurotransmitters receptors Do not bind to receptors NO affects receptors by: Activating enzymes involved int the 2 nd messanger cascade e.g. guanylyl cyclase Modifying the activities of other proteins by nitrosyllating them e.g. NMDA receptors, Na+-K+ ATPase pump 11/22/2019 69

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71. Activity Discuss the NT’s one after the other under the following subheadings: Synthesis Location Receptors Fate Activity/effects Classification Clinical application Discuss synaptic plasticity and learning 11/22/2019 71

72. “Be afraid of remaining stagnant not slow progress.” THANK YOU 11/22/2019 72