1. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Neuroscience: Exploring the Brain, 3e Chapter 5: Synaptic Transmission

2. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Introduction Synaptic Transmission –Information transfer at a synapse –Plays role in all the operations of the nervous system –1897: Charles Sherrington- “synapse” Cajal vs Golgi (1906) –Chemical and electrical synapses 1921- Otto Loewi 1959- Furshpan and Potter

3. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Types of Synapses Direction of Information Flow –In one direction: Neuron to target cell –First neuron = Presynaptic neuron –Target cell = Postsynaptic neuron

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5. Type of Synapses Golgi – Continuous synapse Cajal – Contiguous synapse

7. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins –Gap junction Channel Connexon- formed by six connexins –Cells are said to be “electrically coupled” Flow of ions from cytoplasm to cytoplasm Electrical Synapse

8. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins INSERT FIG. 5.1 (Yes, deliberately out of order)

9. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Electrical Synapse –Very fast transmission Postsynaptic potentials (PSPs) –Synaptic integration: Several PSPs occurring simultaneously to excite a neuron (i.e. causes AP)

10. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Chemical Synapse

11. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Chemical Synapse

12. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins CNS Synapses (Examples) –Axodendritic: Axon to dendrite –Axosomatic: Axon to cell body –Axoaxonic: Axon to axon –Dendrodendritic: Dendrite to dendrite Types of Synapses

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14. CNS Synapses (Examples) –Gray’s Type I: Asymmetrical, excitatory –Gray’s Type II: Symmetrical, inhibitory Types of Synapses

15. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins The Neuromuscular Junction (NMJ) –Studies of NMJ established principles of synaptic transmission Types of Synapses

16. An Actual Neuromuscular Synapse Goodsell, D. S. (2009), Neuromuscular synapse. Biochem. Mol. Biol. Educ., 37: 204–210. doi: 10.1002/bmb.20297

17. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Principles of Chemical Synaptic Transmission Basic Steps –Neurotransmitter synthesis –Load neurotransmitter into synaptic vesicles –Depolarization  Vesicles fuse to presynaptic terminal –Neurotransmitter spills into synaptic cleft –Binds to postsynaptic receptors –Biochemical/Electrical response elicited in postsynaptic cell –Removal of neurotransmitter from synaptic cleft

18. Synaptic Transmission at Neuromuscular Junction

19. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Principles of Chemical Synaptic Transmission Basic Steps –Neurotransmitter synthesis –Load neurotransmitter into synaptic vesicles –Depolarization  Vesicles fuse to presynaptic terminal –Neurotransmitter spills into synaptic cleft –Binds to postsynaptic receptors –Biochemical/Electrical response elicited in postsynaptic cell –Removal of neurotransmitter from synaptic cleft

20. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins –Amino acids: Small organic molecules Neurotransmitters

21. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins –Amino acids: Small organic molecules –Amines: Small organic molecules Neurotransmitters

22. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins –Amino acids: Small organic molecules –Amines: Small organic molecules –Peptides: Short amino acid chains (i.e. proteins) stored in and released from secretory granules Neurotransmitters

23. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins –____ ____: Small organic molecules e.g., Glutamate, Glycine, GABA –____ : Small organic molecules e.g., Dopamine, Acetylcholine, Histamine –____ : Short amino acid chains (i.e. proteins) stored in and released from secretory granules e.g., Dynorphin, Enkephalins Neurotransmitters

24. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Neurotransmitter Synthesis and Storage Loading Neurotransmitters

25. Dense Core Vesicles Goodsell, D. S. (2009), Neuromuscular synapse. Biochem. Mol. Biol. Educ., 37: 204–210. doi: 10.1002/bmb.20297

26. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Exocytosis: Process by which vesicles release their contents Neurotransmitter Release

27. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Process of exocytosis stimulated by release of intracellular calcium, [Ca 2+ ]i Proteins alter conformation - activated Vesicle membrane incorporated into presynaptic membrane Neurotransmitter released Vesicle membrane recovered by endocytosis Mechanism of Neurotransmitter release (Clathrin-mediated endocytosis: http://biochem.web.utah.edu/iwasa/projects/clathrin.html)

28. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins - Ionotropic: Transmitter-gated ion channels Neurotransmitter Receptors and Post- synaptic Response

29. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins –Metabotropic: G-protein-coupled receptor Neurotransmitter Receptors and Post- synaptic Response

30. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins EPSP:Transient postsynaptic membrane depolarization by presynaptic release of neurotransmitter IPSP: Transient hyperpolarization of postsynaptic membrane potential caused by presynaptic release of neurotransmitter Reversal potential Excitatory and Inhibitory Postsynaptic Potentials

31. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins –Diffusion: Away from the synapse –Reuptake: Neurotransmitter re-enters presynaptic axon terminal –Enzymatic destruction inside terminal cytosol or synaptic cleft –Desensitization: despite continued presence of ACh, transmitter-gated channels close Neurotransmitter Recovery and Degradation

32. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins –Effect of drugs on nervous system tissue –Receptor antagonists: Inhibitors of neurotransmitter receptors Curare –Receptor agonists: Mimic actions of naturally occurring neurotransmitters Nicotine –Defective neurotransmission: Root cause of neurological and psychiatric disorders Neuropharmacology

33. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Principles of Synaptic Integration –Process by which multiple synaptic potentials combine within one postsynaptic neuron

34. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins –Synaptic vesicles: Elementary units of synaptic transmission. Almost fixed amount of nerotransmitter Quantum: An indivisible unit –Miniature postsynaptic potential (“mini”) –Quantal analysis: Used to determine number of vesicles that release during neurotransmission –Neuromuscular junction: About 200 synaptic vesicles, EPSP of 40mV or more –CNS synapse: Single vesicle, EPSP of few tenths of a millivolt Quantal Analysis of EPSPs

35. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins –Allows for neurons to perform sophisticated computations –EPSP summation: EPSPs added together to produce significant postsynaptic depolarization –Spatial: EPSP generated simultaneously in different spaces –Temporal: EPSP generated at same synapse in rapid succession Synaptic Integration - EPSP Summation

36. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Synaptic Integration - EPSP Summation

37. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins –Assume: Dendrite as a straight cable (~spinal motor dendrite) Membrane depolarization falls off exponentially with increasing distance V x = V o /e x/ Dendritic length constant (): at which, 37% of Vo –In reality, dendrites are very elaborate structures that contribute to more complex integrative properties The Contribution of Dendritic Properties to Synaptic Integration

38. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins V x =V o * e -x/λ The Contribution of Dendritic Properties to Synaptic Integration

39. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins –Dendrites of neurons: voltage-gated sodium, calcium, and potassium channels Can act as amplifiers (vs. passive) –Dendritic sodium channels: May carry electrical signals in opposite direction, from soma outward along dendrites (Cajal?) Excitable Dendrites

40. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins –Action of synapses to take membrane potential away from action potential threshold –Exerts powerful control over neuron output Inhibition

41. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins –Excitatory vs. inhibitory synapses: Bind different neurotransmitters, allow different ions to pass through channels IPSPs and Shunting Inhibition

42. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins –Excitatory vs. inhibitory synapses: Bind different neurotransmitters, allow different ions to pass through channels –Membrane potential more negative: hyperpolarizing IPSP –E Cl = -65 mV ? Shunting Inhibition: Inhibiting current flow from soma to axon hillock IPSPs and Shunting Inhibition

43. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Shunting Inhibition

44. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins –Excitatory synapses Gray’s type I morphology Spines: Excitatory synapses –Inhibitory synapses Gray’s type II morphology Clustered on soma and near axon hillock The Geometry of Excitatory and Inhibitory Synapses

45. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Concluding Remarks Chemical synaptic transmission –Rich diversity allows for complex behavior –Provides explanations for drug effects –Defective transmission is the basis for many neurological and psychiatric disorders –Key to understanding the neural basis of learning and memory

46. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Question of the Day How stepping on a rusty nail may result in muscle spasms and even eventual death? Hint: It involves synaptic transmission. -In general, what molecular/cellular events happened? Are there effective treatments? -Does the behavior a result of (mostly) defects in inhibitory or excitatory synapse? How do these defects affect synaptic integration?

48. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Principles of Synaptic Integration Modulation –Synaptic transmission that modifies effectiveness of EPSPs generated by other synapses with transmitter- gated ion channels –Example: Activating NE β receptor