Title: Synaptic Plasticity
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3Synaptic Plasticity
4The term synaptic plasticity refers to the
variability of the strength of a signal
transmitted through a synapse.
- Facilitation
- The amplitude of the postsynaptic response
increases when the postsynaptic cell is activated
several times in quick succession - Important Questions
- Presynaptic or Postsynaptic?
- Underlying Mechanisms?
5Time Course of Activity Induced Changes
Synaptic plasticity is classified according to
the duration over which the effect persists.
SHORT TERM CHANGESFacilitation appears
instantly, and is of short duration (100
ms)Depression recovers and Augmentation
dissipates within 10
secondsPost-tetanic potentiation (PTP) can last
for more than 10 minutesLONG TERM
CHANGESLong-term potentiation (LTP) and
Long-term Depression (LTD) last from minutes to
beyond 10 hours
6Short-term Changes in Signaling
- Most extensively studied at synapses in the
peripheral nervous system (chick ciliary
ganglion, skeletal muscle) - Changes have also been demonstrated throughout
the CNS - Facilitation
- Augmentation
- Post-tetanic Potentiation (PTP)
- Depression
- Typically last for periods ranging from
milliseconds (facilitation) to tens of minutes
(PTP).
7Facilitation of Transmitter Release
- Most immediate effect of repetitive stimulation
is synaptic facilitation - Amplitudes of EPPs increase progressively
- The effect outlasts the stimulus train
Frog NMJ
Low Ca2
Cause increased mean number of quanta of
transmitter released by the presynaptic terminal,
probably by increasing the probability of release
and perhaps increasing the number of release
sites.
8Augmentation of Synaptic Transmission
- Slower phase of facilitation
- Increase in synaptic potential amplitude comes on
more slowly than facilitation - Decays over a much longer time period (time
constant of 5-10s)
9Post-Tetanic Potentiation (PTP)
- Relatively long train of high frequency stimuli
(Tetanus) - Refers to increased transmitter (ACh) release
from presynaptic terminal due to prior
stimulation (similar to facilitation and
augmentation) - Differs from facilitation and augmentation in
that its onset is considerably delayed - (reaches maximum several seconds after
stimulation ceases, lasts for tens of minutes - Blocked by removal of calcium from bathing
solution, but PTP occurs in the presence of TTX
(w/ depolarizing pulses)
Curarized
Chick ciliary ganglion
10- The frog neuromuscular junction (NMJ) provides an
excellent model for studying the role of
receptors in synaptic transmission. The
preparation has a large postsynaptic element,
making it relatively easy to monitor changes in
synaptic transmission in the form of end plate
potentials (EPPs). Unlike action potentials, EPPs
are not all-or-none responses instead, they
reflect small changes in synaptic transmission.
To observe EPPs, antagonists must be applied to
the NMJ to compete with neurotransmitter binding
to postsynaptic receptors. This competition
prevents the depolarization of the postsynaptic
membrane from reaching threshold and thus,
eliminates action potentials. - Curare is an example of a non-depolarizing muscle
relaxant which blocks the nicotinic receptors,
one of the two types of cholinergic
(acetylcholine) receptors on the post synaptic
membrane of the neuromuscular junction.
11Depression of Transmitter Release
- Synaptic depression can occur if the number of
quanta released by a train is large - Amplitudes of EPPs decrease progressively with
repetitive stimulation - This effect also outlasts the stimulus train (not
shown)
Curarized
Frog NMJ
High Ca2
Thought to be caused by depletion of vesicles
from the presynaptic terminal during the
conditioning train, and reduced release efficacy.
12Short Term Synaptic Plasticity
- Synaptic enhancement (facilitation,
augmentation, potentiation) - ALL presynaptic mechanisms
- Increase in mean number of transmitter quanta
without change in quantal size or postsynaptic
effectiveness - Increased probability of release and perhaps an
increased number of release sites - Crucial role of calcium
- Residual presynaptic intracellular calcium
- Synaptic depression
- MOSTLY presynaptic
- Depletion of pool of vesicles
- Decrease in number of transmitter quanta
- Decrease in probability of release and perhaps a
reduced release efficacy
13Long-term Changes in Signaling
- In the CNS, repetitive activity produces changes
in synaptic efficiency that last much longer than
seen at peripheral synapses - ranging from
minutes to hours. - Hippocampal LTP best studied of any form of
plasticity. Much of the research predicated on
assumption that hippocampal LTP is the mechanism
for learning. - Cortex both LTP and LTD of pyramidal cell
excitatory synapses - Amygdala LTP closely linked to fear
conditioning - Cerebellum mostly LTD of Purkinje cell EPSPs.
Some LTP at Purkinje cell excitatory synapses
and LTP of inhibitory synapses - May represent neural substrates for learning and
memory - Long-Term Potentiation
- Long-Term Depression
14LTP and LTDin vitro vs. in vivo
- Acute Brain Slice Prep, Slice culture,
Co-Cultured cells - Limitations mimics an intact system
- removal of normal inputs and milieu
- addition of blockers such as picrotoxin or
tetrodotoxin - lack normal outputs
- Advantages clear and interpretable response
- Single EPSP/IPSP is unequivocal its there or
it isnt - No contamination from other inputs
- Intact anesthetized or freely moving animal
- Dont know effective stimulation
- Can study effects of stimulation on behavior
15Long-term Potentiation
Why the hippocampus?
- First described by Bliss and Lomo (1973) at
glutamatergic synapses in the hippocampal
formation. - High frequency stimulation of inputs to dentate
gyrus cells produces an increase in the amplitude
of EPSPs lasting for hours or days. - Homosynaptic LTP
- The LTP effect also observed in neocortex.
16Long-term Potentiation in CA1
Requires only a brief tetanus, is input specific,
and can last many weeks
17Associative LTP and Learning?
Associative LTP is the strengthening of the
connection between two neurons that have been
simultaneously active
18Associative LTP
19Mechanism(s) for LTP in CA1
Increased effectiveness of existing postsynaptic
AMPA receptors, perhaps by phosphorylation. PKC
phosphorylation of the AMPA receptor changes the
protein in some way that increases the ionic
conductance of the channel. Insertion of
completely new AMPA receptors into the
membrane Changes to the structure of the
synapse- new buds form on postsynaptic dendrites,
axons sprout and form multiple synapses.
20Significance of Changes in Synaptic Efficacy
- LTP (and LTD) are of particular interest because
learning and memory are thought to involve
long-term changes in synaptic efficacy. - A number of correlations have been shown between
spatial learning in intact animals and LTP in
hippocampal slices (ie., both blocked by NMDA or
mGlu Receptor antagonists) - LTP in amygdala strongly associated with aversive
(fear) conditioning - rats trained to associate foot shock with a
sound exhibit an exaggerated auditory startle
reflex - cells in the amygdala display LTP-like
increase in their synaptic responses to
stimulation of auditory inputs. - both are blocked by NMDA receptor antagonists.
21Types of Long-term Depression
Linden Connor, 1995
22Cerebellar Anatomy
- EXCITATORY
- Parallel Fibers (gr c.)
- Climbing Fibers
- INHIBITORY
- Purkinje Cells
- Stellate Cells
- Basket Cells
23Long-term Depression in the Cerebellum
After pairing, there is an LTD of the response to
parallel fiber stimulation
24Mechanism of LTD in the Cerebellum
AMPA receptors are internalized Postsynaptic
effect
CF activates Purkinje Cell, Na entry depolarizes
the dendrite, and voltage-gated Ca2 channels are
activated. PF activation (glutamate) also
increases Na entry, through AMPA receptors. The
glutamate also directly activates mGluRs in the
membrane. This generates DAG which activates
PKC. PKC phosphorylates proteins--somehow
leading to a decreased number of AMPA receptors
in the postsynaptic membrane.
25Hebbian Rules for Synaptic ModificationDonald
Hebb(1940s)
- When the presynaptic axon is active, and at the
same time the postsynaptic neuron is strongly
activated by other inputs, then the synapse
formed by the presynaptic axon is strengthened - Neurons that fire together wire together
- When the presynaptic axon is active, and at the
same time the postsynaptic neuron is weakly
activated by other inputs, then the synapse
formed by the presynaptic axon is weakened - Neurons that fire out of sync lose their link