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SYNAPTIC TRANSMISSION

SYNAPTIC TRANSMISSION. D. Introduction. SYNAPTIC TRANSMISSION The process by which neurons transfer information at a synapse Charles Sherrington (1897) : named ‘Synapse’ Chemical synapse vs. Electrical synapse Otto Loewi (1921) : Chemical synapses

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SYNAPTIC TRANSMISSION

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  1. SYNAPTIC TRANSMISSION D

  2. Introduction • SYNAPTIC TRANSMISSION • The process by which neurons transfer information at a synapse • Charles Sherrington (1897) : named ‘Synapse’ • Chemical synapse vs. Electrical synapse • Otto Loewi (1921) : Chemical synapses • Edwin Furshpan and David Potter (1959) : Electrical synapses • John Eccles (1951) : Glass microelectrode

  3. Types of Synapses • Electrical Synapses • Direct transfer of ionic current from one cell to the next • Gap junction • The membranes of two cells are held together by clusters of connexins • Connexon • A channel formed by six connexins • Two connexons combine to from a gap junction channel • Allows ions to pass from one cell to the other • 1-2 nm wide : large enough for all the major cellular ions and many small organic molecules to pass

  4. Types of Synapses • Electrical Synapses • Cells connected by gap junctions are said to be “electrically coupled” • Flow of ions from cytoplasm to cytoplasm bidirectionally • Very fast, fail-safe transmission • Almost simultaneous action potential generations • Common in mammalian CNS as well as in invertebrates

  5. Electrical synapses • Postsynaptic potential (PSP) • Caused by a small amount of ionic current that flow into through the gap junction channels • Bidirectional coupling • PSP generated by a single electrical synapse is small (~1 mV) • Several PSPs occuring simultaneously may excite a neuron to trigger an action potential

  6. Electrical synapses • High temporal precision • Paired recording reveals synchronous voltage responses upon depolarizing or hyperpolarizing current injections • Often found where normal function requires that the neighboring neurons be highly synchronized • Oscillations, brain rhythm, state dependent…

  7. Types of Synapses • Chemical Synapses • Synaptic cleft : 20-50 nm wide (gap junctions : 3.5 nm) • Adhere to each other by the help of a matrix of fibrous extracellular proteins in the synaptic cleft • Presynaptic element (= axon terminal) contains • Synaptic vesicles • Secretory granules (~100nm) (=dense-core vesicles) • Membrane differentiations • Active zone • Postsynaptic density

  8. Chemical Synapses vs Electrical synapses

  9. Types of Synapses • Axoaxonic: Axon to axon • Dendrodendritic: Dendrite to dendrite • CNS Synapses • Axodendritic: Axon to dendrite • Axosomatic: Axon to cell body

  10. Types of Synapses • CNS Synapses • Gray’s Type I: Asymmetrical, excitatory • Gray’s Type II: Symmetrical, inhibitory

  11. Types of Synapses • The Neuromuscular Junction (NMJ) • Synapses between the axons of motor neurons of the spinal cord and skeletal muscle • Studies of NMJ established principles of synaptic transmission • Fast and reliable synaptic transmission(AP of motor neuron always generates AP in the muscle cell it innervates) thanks to the specialized structural features • The largest synapse in the body • Precise alignment of synaptic terminals with junctional folds

  12. Principles of Chemical Synaptic Transmission • Basic Steps • Neurotransmitter synthesis • Load neurotransmitter into synaptic vesicles • 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 • Must happen RAPIDLY!

  13. Principles of Chemical Synaptic Transmission • Neurotransmitters • Amino acids • Amines • Peptides

  14. Principles of Chemical Synaptic Transmission • Neurotransmitters • Amino acids and amines are stored in synaptic vesicles • Peptides are stored in and released from secretory granules • Often coexist in the same axon terminals • Fast synaptic transmission and slower synaptic transmission

  15. Principles of Chemical Synaptic Transmission • Neurotransmitter Synthesis and Storage • Natural building blocks vs specialized neurotransmitters

  16. Principles of Chemical Synaptic Transmission • Neurotransmitter Release • Voltage-gated calcium channels open - rapid increase from 0.0002 mM to greater than 0.1 mM • Exocytosis can occur very rapidly (within 0.2 msec) because Ca2+ enters directly into active zone • ‘Docked’ vesicles are rapidly fused with plasma membrane • Protein-protein interactions regulate the process (e.g. SNAREs) of ‘docking’ as well as Ca2+- induced membrane fusion • Vesicle membrane recovered by endocytosis

  17. Principles of Chemical Synaptic Transmission • Neurotransmitter Release • Reserve pool and Readily releasable pool (RRP)

  18. Fig. 1. Scattered distribution of RRP vesicles S. O. Rizzoli et al., Science 303, 2037 -2039 (2004) Published by AAAS

  19. Principles of Chemical Synaptic Transmission • Neurotransmitter Release • Secretory granules • Released from membranes that are away from the active zones • Requires high-frequency trains of action potentials to be released • Ca2+ needs to be build up throughout the axon terminal • Leisurely process (50 msec)

  20. Principles of Chemical Synaptic Transmission • Neurotransmitter receptors: • Ionotropic: Transmitter-gated ion channels • Ligand-binding causes a slight conformational change that leads to the opening of channels • Not as selective to ions as voltage-gated channels • Depending on the ions that can pass through, channels are either excitatory or inhibitory • Reversal potential

  21. Principles of Chemical Synaptic Transmission • Excitatory and Inhibitory Postsynaptic Potentials: • EPSP:Transient postsynaptic membrane depolarization by presynaptic release of neurotransmitter • Ach- and glutamate-gated channels cause EPSPs

  22. Principles of Chemical Synaptic Transmission • Excitatory and Inhibitory Postsynaptic Potentials: • IPSP: Transient hyperpolarization of postsynaptic membrane potential caused by presynaptic release of neurotransmitter • Glycine- and GABA-gated channels cause IPSPs

  23. Principles of Chemical Synaptic Transmission • Metabotropic: G-protein-coupled receptors • Trigger slower, longer-lasting and more diverse postsynaptic actions • Same neurotransmitter could exert different actions depending on what receptors it bind to • Autoreceptors: present on the presynaptic terminal • Typically, G-protein coupled receptors • Commonly, inhibit the release or synthesis of neurotransmitter • Negative feedback Effector proteins

  24. Principles of Chemical Synaptic Transmission • Neurotransmitter Recovery and Degradation • Clearing of neurotransmitter is necessary for the next round of synaptic transmission • Simple Diffusion • Reuptake aids the diffusion • Neurotransmitter re-enters presynaptic axon terminal or enters glial cells through transporter proteins • The transporters are to be distinguished from the vesicular forms • Enzymatic destruction • In the synaptic cleft • Acetylcholinesterase (AchE) • Desensitization: • Channels close despite the continued presence of ligand • Can last several seconds after the neurotransmitter is cleared • Nerve gases (e.g. sarin) inhibit AchE - increased Ach - AchR desensitization - muscle paralysis

  25. Principles of Chemical Synaptic Transmission • Neuropharmacology • The study of effect of drugs on nervous system tissue • Receptor antagonists: Inhibitors of neurotransmitter receptors • e.g. Curare binds tightly to Ach receptors of skeletal muscle • Receptor agonists: Mimic actions of naturally occurring neurotransmitters • E.g. Nicotine binds and activates the Ach receptors of skeletal muscle (nicotinic Ach receptors) • Toxins and venoms • Defective neurotransmission: Root cause of neurological and psychiatric disorders

  26. Principles of Synaptic Integration • Synaptic Integration • Process by which multiple synaptic potentials combine within one postsynaptic neuron • Basic principle of neural computation • The Integration of EPSPs - + - + + -

  27. Principles of Synaptic Integration • The integration of EPSPs • Quantal Analysis of EPSPs • Synaptic vesicles: Elementary units of synaptic transmission • Contains the same number of transmitter molecules (several thousands) • Postsynaptic EPSPs at a given synapse is quantized = The amplitude of EPSP is an integer multiple of the quantum • Quantum: An indivisible unit determined by • the number of transmitter molecules in a synaptic vesicle • the number of postsynaptic receptors available at the synapse • Miniature postsynaptic potential (“mini”) is generated by spontaneous, un-stimulated exocytosis of synaptic vesicles • 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

  28. Principles of Synaptic Integration • EPSP Summation • Allows for neurons to perform sophisticated computations • Integration: EPSPs added together to produce significant postsynaptic depolarization • Spatial summation : adding together of EPSPs generated simultaneously at different synapses • Temporal summation : adding together of EPSPs generated at the same synapse in rapid succession (within 1-15 msec of one another)

  29. Principles of Synaptic Integration • The Contribution of Dendritic Properties to Synaptic Integration • Dendrite as a straight cable : EPSPs have to travel down to spike-initiation zone to generate action potential • Membrane depolarization falls off exponentially with increasing distance • Vx = Vo/ex/ λ • Vo : depolarization at the origin • λ : Dendritic length constant • Distance where the depolarization is 37% of origin (Vλ= 0.37 Vo) • In reality, dendrites have branches, changing diameter..

  30. Principles of Synaptic Integration • The Contribution of Dendritic Properties to Synaptic Integration • Length constant (λ) • An index of how far depolarization can spread down a dendrite or an axon • Depends on two factors • internal resistance (ri) : the resistance to current flowing longitudinally down the dendrite • membrane resistance (rm) : the resistance to current flowing across the membrane • While ri is relatively constant (largely determined by the diameter of dendrite and electrical property of cytoplasm) in a mature neuron, rm changes from moment to moment (depends on the number of opne channels) • Excitable Dendrites • Dendrites of neurons having voltage-gated sodium, calcium, and potassium channels • Can act as amplifiers (vs. passive) : EPSPs that are large enough to open voltage-gated channels can reach the soma by the boost offered by added currents through VGSCs • Dendritic sodium channels: May carry electrical signals in opposite direction, from soma outward along dendrites : back-propagating action potential might inform the dendrites that an action potential has been generated

  31. Principles of Synaptic Integration • Inhibition Action of synapses to take membrane potential away from action potential threshold • IPSPs and Shunting Inhibition • Excitatory vs. inhibitory synapses: Bind different neurotransmitters, allow different ions to pass through channels • GABA or glycine :: Cl- • Ecl : -65 mV, at resting membrane potential no IPSP is visible

  32. Principles of Synaptic Integration • Shunting Inhibition • Inhibiting current flow from soma to axon hillock • The Geometry of Excitatory and Inhibitory Synapses • Inhibitory synapses • Gray’s type II morphology • Clustered on soma and near axon hillock • Powerful position to influence the activity of the postsynaptic neuron

  33. Principles of Synaptic Integration • Modulation • Synaptic transmission that does not directly evoke EPSPs and IPSPs but instead modifies the effectiveness of EPSPs generated by other synapses with transmitter-gated ion channels • Mediated by G-protein-coupled neurotransmitter receptors • Example: Activating NE β receptor

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