lecture 21: long term synaptic plasticity Flashcards
What causes synaptic strength to change?
Diseases (myasthenia gravis, startle disease…)
* Drugs (therapeutic, recreational…)
* Prior or ongoing activity (experience…learning)
What mechanisms lead to altered synaptic strength?
Rapid change in synaptic efficacy with no structural change
(Short-term plasticity and modulation)
* Growth or shrinkage of synapse or receptors (Early long-term
plasticity)
* Addition or loss of synapses (Late long-term plasticity)
(Short-term plasticity and modulation)
Rapid change in synaptic efficacy with no structural change
(Early long-term
plasticity)
Growth or shrinkage of synapse or receptors
(Late long-term plasticity)
Addition or loss of synapses
Which of the following would not cause a change in synaptic strength
a. Increasing the quantal content
b. Increasing the number of post-synaptic receptors
c. Increasing the conductance of a synaptic receptor
d. Increasing the myelination and conduction speed of the
presynaptic axon.
. Increasing the myelination and conduction speed of the
presynaptic axon
Long-term Potentiation (LTP):
brief high-frequency
stimulation (tetanus) produces a long-lasting increase in
synaptic strength
Functions of Hippocampus
memory consolidation (HM), spatial navigation (place cells) – Memory Lecture
* One of the most thoroughly studied areas of the mammalian brain due to highly structured
synaptic circuitry
* Highly laminated structure (very orderly layers) – forms a “horn like path”.
* Synaptic pathway lies in a thin plane – lends itself to neuroanatomical and
electrophysiological studies
Hippocampal circuitry
- Acute slices of the hippocampus
contain intact synaptic connections
that can be tested for plasticity - Granule cells in the dentate gyrus synapse onto CA3 cells.
- CA3 cells synapse onto CA1 cells.
- Both Long Term Potentiation (LTP) and Long Term Depression (LTD) are prevalent in the hippocampus
Changing the strength of a synapse (LTP)
- Stimulating individual axons sporadically
(~once every 30 sec) produces stable responses - High frequency stimulation (tetanus) produces
LTP of the axons that received high frequency
stimulation only. - The axons not active during the high frequency
stimulation (Stimulus 2 above) do not
potentiate
types of short term plasticity
facilitation increases quantal content
depression decreases quantal content due to vesicle depletion
Tetanus
repeated, high
frequency stimulus that leads to ltp (e.g. 100 AP in 1 s)
explain why LTP is specific
LTP requires activity in both the presynaptic
and postsynaptic neurons
explain why LTP is associative
- LTP can act associatively, if a weak synapse is
stimulated along with a strong synapse, both
can be potentiated
what is the makeup of nmda receptors
- NMDA receptors are glutamate-gated ionotropic receptors
NMDA receptors are Ca2+ permeable
- NMDA receptors do not desensitize
what ion blocks the pore of nmda receptors at hyperpolarized potentials (near Vrest)
Mg2+
NMDA receptors are coincidence detectors
- Mg2+ blocks the pore at hyperpolarized potentials (near Vrest)
- When the cell depolarizes, Mg2+ leaves the pore and ions can flow through the channel
- Detects the coincidence of
- Presynaptic release (glutamate)
& - Postsynaptic activity (strong depolarization)
NMDA receptors are permeable to all
of the following ions except ____ .
a. Calcium
b. Magnesium
c. Potassium
d. Sodium
b. Magnesium
Calcium coming in through NMDA receptors leads
to activation of which protein kinases
Protein kinase C,
CamKII
explain how Calcium entry causes a signaling cascade in the postsynaptic cell
- Calcium coming in through NMDA receptors leads
to activation of protein kinases (Protein kinase C,
CamKII) - Kinases phosphorylate AMPA receptors (larger
EPSP) - Additional AMPA receptors are quickly inserted into
the membrane - AMPA receptors are stored in a “recycling endosome”
near the postsynaptic density - No change in NMDA receptor expression
- These changes in synaptic strength last for several
hours
how does protein synthesis during late-LTP produce
structural changes
- Elevated protein kinases can
send a signal to the nucleus –
changing transcriptional
regulation. - New genes get transcribed
- “Immediate early genes” get
expressed very early - Cytoskeleton binding proteins
(spine shape, size, motility, etc) - Anchoring/scaffold proteins
(expand/organize the PSD, lock in new receptors, etc)
how do dendritic spines change after ltp
- Spines get brighter/larger
after LTP
Experimental evidence supporting LTP as a
memory mechanism
Blocking LTP induction mechanisms (NMDA receptors, kinases, etc. )
should impair acquisition of new memories while keeping older
memories intact
* D-AP5 is an NMDA antagonist
* Prevents LTP in the hippocampus
* Also impairs spatial learning – Morris water maze
what induces ltd
prolonged, low frequency stimulation
what does ltd cause
In hippocampal synapses, stimulating at a low frequency (once per second) for several minutes can decrease synaptic strength
* Also dependent on NMDA receptors
* Small, prolonged Ca2+ activates other enzymes:
phophatases
* Causes removal ofAMAP receptors and eventual pruning of spines
how do calcium dynamics lead to either LTP or LTD
- Ca2+ concentration at the spine determines LTD or LTP
- Low frequency presynaptic firing (~ 1-10 Hz) causes a
moderate increase in calcium over a long period of
time, activating phosphatases and triggering LTD - High frequency presynaptic firing (~50-100 Hz) causes a
large sudden increase in calcium activating kinases and
triggering LTP
Hebb’s Postulate
the idea that the
timing of the pre and post synaptic firing of action potentials can alter the
synaptic strength. Summarized as Neurons that fire together, wire together and Neurons out of synch, lose their
link
Long term plasticity
persistent changes in the strength of synaptic
connectivity lasting hours, days, or longer
hippocampus location and function
area of the mammalian
brain, embedded deep in the temporal lobe, that is particularly important in
memory formation and/or retrieval. The hippocampus has also been shown to be responsible for spatial learning and navigation
Dissected slices of the hippocampus contain intact synaptic connections. Long term
potentiation (see below) was first discovered in the hippocampus and it continues to be an important area for plasticity studies. Most of the mechanisms that we will learn occur at the synapse from the “CA3” neurons to the CA1 neurons
NMDA receptor
subtype of glutamate receptor that is typically permeable to K+, Na+ and Ca2+. Extracellular Mg2+ blocks the pore of NMDA receptors at negative membrane potentials, so the channel acts as a coincidence detector: both glutamate (presynaptic
release) and postsynaptic depolarization are required for current to flow through
the channel
Long term potentiation
a sustained strengthening of synaptic connections caused by previous patterns of neuronal and synaptic activity
repeated at synapses in the hippocampus
At the CA3 to CA1 synapse in the
hippocampus, frequent calcium entry through NMDA receptors causes a signaling cascade that includes the activation of
protein kinases and eventually leads to insertion of additional AMPA receptors to the
postsynaptic membrane. These early changes can occur within minutes and later during the later stages of LTP there can be
the growth and even sprouting of additional synaptic connections (spines)
Late LTP
hours after the initial repeated
stimulation that induces LTP, structural
changes in the synapse occur, including
spine motility, an increase in spine size, and
insertion of new spines. Late stages of LTP
involve protein synthesis
Long term depression
a sustained
weakening of synaptic connections caused
by previous patterns of neuronal and synaptic activity - usually repeated stimulations at a lower frequency (e.g. 1 presynaptic action potentials every second
for 5 min). Several different mechanisms have been found underlying LTD at different synapses. In the hippocampus, small, spaced activation and opening of NMDA channels leads to a signaling cascade which eventually causes the internalization of AMPA receptors
Calcium signaling
it may seem contradictory that both LTP and LTD can be triggered by calcium ions flowing into the cell through NMDA receptors, but it is important to consider how much calcium is entering the cell and for how long. A sustained, modest increase in calcium
concentration activates protein phophatases (PP2A and Calcineurin) and leads to a decrease in receptors and a smaller postsynaptic response, while a large, brief increase in the calcium concentration triggers kinases (CaMKII and Protein kinase C) which leads to more receptors and a stronger postsynaptic response (and also suppress or overrides any LTD responses)
- Describe how LTP is initiated and recorded in the hippocampus.
- Diagram or list the signaling cascade from glutamate release to insertion of AMPA
receptors and eventual structural changes that leads to LTP in the hippocampus.
- Explain how NMDA receptors act like coincidence detectors.
- Discuss how the same signal, Ca2+ entry through NMDA receptors, can trigger both LTD
and LTP.
- Explain what aspects of LTP (or LTD) make it a promising substrate of learning and
memory
Experimental evidence supporting LTP as a
memory mechanism.
Blocking LTP induction mechanisms (NMDA receptors, kinases, etc. )
should impair acquisition of new memories while keeping older
memories intact
* Saturating LTP should also impair the acquisition of new memories
* Selective erasure of potentiation (or invoking LTD) should disrupt the
retention of established memories but not impair the acquisition of
new information
