SYNAPTIC TRANSMISSION

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SYNAPTIC TRANSMISSION
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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

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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

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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

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• 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

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• 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

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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

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• Chemical Synapses vs Electrical synapses

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Types of Synapses

• Axoaxonic Axon to axon
• Dendrodendritic Dendrite to dendrite

• CNS Synapses
• Axodendritic Axon to dendrite
• Axosomatic Axon to cell body

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Types of Synapses

• CNS Synapses
• Grays Type I Asymmetrical, excitatory
• Grays Type II Symmetrical, inhibitory

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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

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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!

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Principles of Chemical Synaptic Transmission

• Neurotransmitters
• Amino acids
• Amines
• Peptides

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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

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Principles of Chemical Synaptic Transmission

• Neurotransmitter Synthesis and Storage
• Natural building blocks vs specialized
  neurotransmitters

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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

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Principles of Chemical Synaptic Transmission

• Neurotransmitter Release
• Reserve pool and Readily releasable pool (RRP)

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

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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

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Principles of Chemical Synaptic Transmission

• Excitatory and Inhibitory Postsynaptic
  Potentials

• EPSPTransient postsynaptic membrane
  depolarization by presynaptic release of
  neurotransmitter
• Ach- and glutamate-gated channels cause EPSPs

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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

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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
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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

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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

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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 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

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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)

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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/ ?

• Vo depolarization at the origin
• ? Dendritic length constant
• Distance where the depolarization is 37 of
  origin (V? 0.37 Vo)
• In reality, dendrites have branches, changing
  diameter..

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Principles of Synaptic Integration

• The Contribution of Dendritic Properties to
  Synaptic Integration
• Length constant (?)
• 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

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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

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Principles of Synaptic Integration

• Shunting Inhibition
• Inhibiting current flow from soma to axon hillock
• The Geometry of Excitatory and Inhibitory
  Synapses
• Inhibitory synapses
• Grays type II morphology
• Clustered on soma and near
  axon hillock
• Powerful position to influence
  the activity of
  the
  postsynaptic neuron

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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 ß receptor