Neural Zones

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Neural Zones
Figure 5.2
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How Neurons connect
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The Synapse

• A functional connection between surfaces
• Signal transmission zone
• Synapse synaptic cleft, presynaptic cell, and
  postsynaptic cell
• Synaptic cleft space in between the presynaptic
  and postsynaptic cell
• Postsynaptic cell neurons, muscles, and
  endocrine glands
• Neuromuscular junction synapse between a motor
  neuron and a muscle

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The Synapse

• Axon terminal found in motor neurons
• Axon varicosities ie swellings. Arranged like
  beads on a string and contain neurotransmitter
  containing vesicles
• En passant synapse CNS. Consists of a swelling
  along the axon
• Spine synapse presynaptic cell connects with a
  dendritic spine on the dendrite of the
  postsynaptic cell

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The Synapse

• Axodentritic between axon terminal of one neuron
  and the dendrite of another
• Axosomatic between the axon terminal of one
  neuron and the cell body of another
• Dendrodendritic between dendrites of neurons
  (often are electricla synapses)
• Axoaxonic between an axon terminal of a
  presynatpic neuron and the axon of a postsynaptic
  neuron.

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Diversity of Signal Conduction

• So far
• Electrotonic
• Action potentials
• Saltatory conduction
• Chemical and electrical synapses

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Diversity of Synaptic Transmission
Figure 5.26
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Electrical and Chemical Synapses
Electrical synapse Chemical synapse
Rare in complex animals Common in complex animals
Common in simple animals Rare in simple animals
Fast Sloooooow
Bi-directional ? Unidirectional ?
Postsynaptic signal is similar to presynaptic Postsynaptic signal can be different
Excitatory Excitatory or inhibitory
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Electrical synapses

• cells connect via gap junctions
• membranes are separated by 2 nm
• gap junctions link the cytosol of two cells
• provide a passageway for movement of very
• small molecules and ions between the cells
• gap junction channels have a large conductance
• NO synaptic delay (current spread from cell to
  cell is instantaneous) - important in some
  reflexes
• chemical synapses do have a significant delay ie
  slow
• commonly found in other cell types as well i.e.
  glia
• can be modulated by intracellular Ca2 , pH,
  membrane voltage, calmodulin
• clusters of proteins that span the gap such that
  ions and small molecules can pass directly from
  one cell to another 

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More about electrical synapses
cells connect via gap junctions - made up of 6
protein subunits arranged around a central pore,
made up of the connexin protein - the two sides
come together to make a complete unit of 12
proteins around the central pore
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Chemical Synapse Diversity

• Vary in structure and location

Figure 5.27
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Chemical Synapse

• most common type of synapse
• electrical signal in the presynaptic cell is
  communicated to the postsynaptic cell by a
  chemical (the neurotransmitter)
• separation between presynaptic and postsynaptic
  membranes is about 20 to 30 nm
• a chemical transmitter is released and diffuses
  to bind to receptors on postsynaptic side
• bind leads (directly or indirectly) to changes in
  the postsynaptic membrane potential (usually by
  opening or closing transmitter sensitive ion
  channels)
• the response of the neurotransmitter receptor can
  depolarizes (excitatory postsynaptic potential
  epsp) or hyperpolarizes (inhibitory postsynaptic
  potential ipsp) the post-synaptic cell and
  changes its activity
• significant delay in signal (1 msec) but far more
  flexible than electrical synapse  

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More about chemical Synapses

• Some types of chemical synapse include
• Excitatory - excite (depolarize the postsynaptic
  cell
• Inhibitory - inhibit (hyperpolarize the
  postsynaptic cell)
• Modulatory - modulates the postsynaptic cells
  response to other synapses

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General sequence of events







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General sequence of events
1. Nerve impulse arrives at presynaptic terminal
2. Depolarization causes voltage-gated Ca 2
channels to open- increases Ca 2 influx, get a
transient elevation of internal Ca 2 100 mM 3.
Vesicle exocytosis- increase in Ca 2 induces
fusion of synaptic vesicles to membrane-
vesicles contain neurotransmitters 4. Vesicle
fusion to membrane releases stored
neurotransmitter 5. Transmitter diffuses across
cleft to postsynaptic side 6. Neurotransmitters
bind to receptor eitheri) ligand-gated ion
channel or ii) receptors linked to 2nd messenger
systems 7. Binding results in a conductance
change - channels open or close or - binding
results in modulation of postsynaptic side
Cont.
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General sequence of events
8. Postsynaptic response - change in membrane
potential (e.g. muscle contraction in the case of
a motorneuron at a neuromuscular junction) 9.
Neurotransmitter is removed from the cleft by two
mechanismsi) transmitter is destroyed by an
enzyme such as acetylcholine esteraseii)
transmitter is taken back up into the presynaptic
cell and recyclede.g. - acetylcholine esterase,
breaks down acetylcholine in cleft, choline is
recycled back into the presynaptic terminal
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Neurotransmitters

• Characteristics
• Synthesized in neurons
• Released at the presynaptic cell following
  depolarization
• Bind to a postsynaptic receptor and causes an
  effect

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Neurotransmitters, Cont.

• More than 50 known substances
• Categories
• Amino acids
• Neuropeptides
• Biogenic amines
• Acetylcholine
• Miscellaneous ..
• Neurons can synthesize many kinds of
  neurotransmitters

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Neurotransmitters
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Neurotransmitters cont.
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Signal Strength

• Influenced by neurotransmitter amount and
  receptor activity
• Neurotransmitter amount Rate of release vs. rate
  of removal
• Release due to frequency of APs
• Removal
• Passive diffusion out of synapse
• Degradation by synaptic enzymes
• Uptake by surrounding cells
• Receptor activity density of receptors on
  postsynaptic cell

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Graded Potentials via Neurotransmitters

• Vary in magnitude depending on the strength of
  the stimulus
• e.g., more neurotransmitter ? more ion channels
  will open
• Can depolarize (Na and Ca2 channels) or
  hyperpolarize (K and Cl- channels) the cell

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Graded Potentials
Figure 5.4
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Graded Potentials Travel Short Distances
Figure 5.6
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Neurotransmitter Receptor Function

• Ionotropic
• Ligand-gated ion channels
• Fast
• e.g., nicotinic ACh
• Metabotropic
• Channel changes shape
• Signal transmitted via secondary messenger
• Ultimately sends signal to an ion channel
• Slow
• Long-term changes

Figure 5.28
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Second Messenger again

• When activated by a ligand the catalytic domain
  starts a phosphorylation cascade
• Named based on the reaction catalyzed

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Second Messengers to know
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Neurotransmitter receptors

• Different types of neurotransmitter receptors
• Functional Type Ligand Ion Channel
• Excitatory Receptors Acetylcholine Na/K 
• Glutamate Na/K Ca2 
• Glutamate Na/K 
• Serotonin Na/K
• Inhibitory Receptors Aminobutyric acid, GABA
  Cl- 
• Glycine Cl-

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Amount of Neurotransmitter

• Influenced by AP frequency which influences Ca2
  concentration
• Control of Ca2
• Open voltage-gated Ca2 channels ? Ca2
• Binding with intracellular buffers ? Ca2
• Ca2 ATPases ? Ca2
• High AP frequency ? influx is greater than
  removal ? high Ca2 ? many synaptic vesicles
  release their contents ? high neurotransmitter

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Removal of Neurotransmitter

• broken down by enzyme
• - acetylcholine esterase breaks down
  acetylcholine in the synaptic cleft
• - many nerve gases and insecticides work by
  blocking acetylcholine esterase Yikes!
• - prolongs synaptic communication
• b) recycled by uptake
• - most neurotransmitters are removed by
  Na/neurotransmitter symporters
• - due to a specific neurotransmitter transporter
• - recycled by uptake into presynaptic terminal
  or other cells  (glial cells will take up
  neurotransmitters)
• c) diffusion simple diffusion away from site
   

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Neurotransmitters - stages

• Synthesis
• - all small chemical neurotransmitters are made
  in the nerve terminal
• - responsible for fast synaptic signalling
• - synthetic enzymes precursors transported
  into nerve terminal
• - subject to feedback inhibition (from recycled
  neurotransmitters
• - can be stimulated to increase activity (via
  Ca2 stimulated phosphorylation)
• 2. Packaging into vesicles
• - neurotransmitters packaged into vesicles
• - packaged in small "classical" vesicles
• - involves a pump powered by a pH gradient
  between outside and inside of vesicle
• - pump blocked by drugs and these block
  neurotransmitter release

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Presynaptic vesicles
Two groups  i) low molecular weight, non-peptide
 e.g. acetylcholine, glycine, glutamate  ii)
neuropeptide (over 40 identified so far and
counting..) 
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Presynaptic vesicles

• There are 2 types of secretory vesicles
• We will only talk about small chemical synaptic
  vesicles
• Neuropeptides are made and packaged in the cell
  body and transported to synapse)
• Small chemical neurotransmitter vesicles
• responsible for fast synaptic signaling
• store non-peptide neurotransmitters,   e.g.
  acetylcholine, glycine, glutamate
• enough vesicles in the typical nerve terminal to
  transmit a few thousand impulses
• exocytosis only occurs after an increase of
  internal Ca 2 (due to depolarization) and at
  active zones (regions in the presynaptic
  membrane adjacent to the cleft) 

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Presynaptic vesicles








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Vesicle Exocytosis

• A group of 6 to 7 proteins work together to
  respond to Ca 2 influx and regulate vesicle
  fusion
• after exocytosis the synaptic vesicle membranes
  are reinternalized by endocytosis and reused
  (reloaded with neurotransmitter by a transmitter
  transporter system)
• vesicles are also transported from the cell body
  to the nerve terminal- transmitter is
  synthesized in the terminal and loaded into the
  vesicles- enzymes and substrates necessary are
  present in the terminal- i.e. acetylcholine,
  acetyl-CoA choline used by choline
  acetyltransferase 

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Vesicle Exocytosis

• non-peptide transmitters
• exocytosis only occurs after an increase of
  internal Ca 2 (due to depolarization)
• at active zones (regions in the presynaptic
  membrane adjacent to the synaptic cleft)
• peptide-transmitters (same as for non-peptide
  transmitters except)
• exocytosis is NOT restricted to active zones
• exocytosis is triggered by trains of action
  potentials 

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SNARE hypothesis
The SNARE Hypothesis for Transport Vesicle
Targeting and Fusion
SNARE is an acronym for SNAP receptor (SNAP
stands for soluble N-ethylmaleimide-sensitive
factor attachment proteins).
SNARES are involved in the mediation of protein
transport between various plant organelles by
small membrane vesicles.
Two families i) V-SNARE - vesicle membrane
proteinsii) T-SNARE - target membrane proteins
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SNARE hypothesis

• Vesicle docking occurs between the V-SNARE and
  T-SNARE proteins
• The combined proteins act as a receptor for an
  ATPase that utilizes ATP to generate the "docked"
  form
• One of the proteins is a Ca2 sensor such that
  when Ca2 enters the synapse the vesicle fuses
  with the plasma membrane and releases its
  contents
• The membrane and proteins are then recycled
  through endocytosis (clatharin coat and dynamin
  etc.) and reused.

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Acetylcholine

• Primary neurotransmitter at the vertebrate
  neuromuscular junction

Figure 5.17
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Synaptic Plasticity

• Change in synaptic function in response to
  patterns of use
• Synaptic facilitation ? APs ? ?
  neurotransmitter release
• Synaptic depression ? APs ? ? neurotransmitter
  release
• Post-tetanic potentiation (PTP) after a train
  of high frequency APs ? ? neurotransmitter release

Figure 5.32
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Long-term potentiation
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Postsynaptic Cells

• Have specific receptors for specific
  neurotransmitters
• e.g., Nicotinic ACh receptors

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Diversity of Signal Conduction

• So far
• Electrotonic
• Action potentials
• Saltatory conduction
• Chemical and electrical synapses
• Also
• Shape and speed of action potential
• Due to diversity of Na and K channels

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Ion Channel Isoforms

• Multiple isoforms
• Encoded by many genes
• Variants of the same protein
• Voltage-gated K channels are highly diverse (18
  genes encode for 50 isoforms in mammals)
• Na channels are less diverse (11 isoforms in
  mammals)

Table 5.2
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Channel Density

• Higher density of voltage-gated Na channels
• Lower threshold
• Shorter relative refractory period

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Voltage-Gated Ca2 Channels

• Open at the same time or instead of voltage-gated
  Na channels
• Ca2 enters the cell causing a depolarization
• Ca2 influx is slower and more sustained
• Slower rate of APs due to a longer refractory
  period
• Critical to the functioning of cardiac muscle