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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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introduction
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
slide3

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
slide4

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
slide5
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
slide6
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…
slide7

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
types of synapses
Types of Synapses
  • Axoaxonic: Axon to axon
  • Dendrodendritic: Dendrite to dendrite
  • CNS Synapses
    • Axodendritic: Axon to dendrite
    • Axosomatic: Axon to cell body
types of synapses1
Types of Synapses
  • CNS Synapses
    • Gray’s Type I: Asymmetrical, excitatory
    • Gray’s Type II: Symmetrical, inhibitory
types of synapses2
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
principles of chemical synaptic transmission
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!
principles of chemical synaptic transmission1
Principles of Chemical Synaptic Transmission
  • Neurotransmitters
    • Amino acids
    • Amines
    • Peptides
principles of chemical synaptic transmission2
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
principles of chemical synaptic transmission3
Principles of Chemical Synaptic Transmission
  • Neurotransmitter Synthesis and Storage
    • Natural building blocks vs specialized neurotransmitters
principles of chemical synaptic transmission4
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
principles of chemical synaptic transmission5
Principles of Chemical Synaptic Transmission
  • Neurotransmitter Release
    • Reserve pool and Readily releasable pool (RRP)
slide20

Fig. 1. Scattered distribution of RRP vesicles

S. O. Rizzoli et al., Science 303, 2037 -2039 (2004)

Published by AAAS

principles of chemical synaptic transmission6
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)
principles of chemical synaptic transmission7
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
principles of chemical synaptic transmission8
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
principles of chemical synaptic transmission9
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
slide25

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

principles of chemical synaptic transmission10
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
principles of chemical synaptic transmission11
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
principles of synaptic integration
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

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principles of synaptic integration1
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
principles of synaptic integration2
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)
principles of synaptic integration3
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..
principles of synaptic integration4
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
principles of synaptic integration5
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
principles of synaptic integration6
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
principles of synaptic integration7
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