lecture 21: long term synaptic plasticity

Question 1

What causes synaptic strength to change?

Answer 1

Diseases (myasthenia gravis, startle disease…)
* Drugs (therapeutic, recreational…)
* Prior or ongoing activity (experience…learning)

Question 2

What mechanisms lead to altered synaptic strength?

Answer 2

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)

Question 3

(Short-term plasticity and modulation)

Answer 3

Rapid change in synaptic efficacy with no structural change

Question 4

(Early long-term
plasticity)

Answer 4

Growth or shrinkage of synapse or receptors

Question 5

(Late long-term plasticity)

Answer 5

Addition or loss of synapses

Question 6

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.

Answer 6

. Increasing the myelination and conduction speed of the
presynaptic axon

Question 7

Long-term Potentiation (LTP):

Answer 7

brief high-frequency
stimulation (tetanus) produces a long-lasting increase in
synaptic strength

Question 8

Functions of Hippocampus

Answer 8

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

Question 9

Hippocampal circuitry

Answer 9

• 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

Question 10

Changing the strength of a synapse (LTP)

Answer 10

• 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

Question 11

types of short term plasticity

Answer 11

facilitation increases quantal content

depression decreases quantal content due to vesicle depletion

Question 12

Tetanus

Answer 12

repeated, high
frequency stimulus that leads to ltp (e.g. 100 AP in 1 s)

Question 13

explain why LTP is specific

Answer 13

LTP requires activity in both the presynaptic
and postsynaptic neurons

Question 14

explain why LTP is associative

Answer 14

• LTP can act associatively, if a weak synapse is
  stimulated along with a strong synapse, both
  can be potentiated

Question 15

what is the makeup of nmda receptors

Answer 15

• NMDA receptors are glutamate-gated ionotropic receptors

NMDA receptors are Ca2+ permeable

• NMDA receptors do not desensitize

Question 16

what ion blocks the pore of nmda receptors at hyperpolarized potentials (near Vrest)

Answer 16

Mg2+

Question 17

NMDA receptors are coincidence detectors

Answer 17

• 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)

Question 18

NMDA receptors are permeable to all
of the following ions except ____ .
a. Calcium
b. Magnesium
c. Potassium
d. Sodium

Answer 18

b. Magnesium

Question 19

Calcium coming in through NMDA receptors leads
to activation of which protein kinases

Answer 19

Protein kinase C,
CamKII

Question 20

explain how Calcium entry causes a signaling cascade in the postsynaptic cell

Answer 20

• 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

Question 21

how does protein synthesis during late-LTP produce
structural changes

Answer 21

• 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)

Question 22

how do dendritic spines change after ltp

Answer 22

• Spines get brighter/larger
  after LTP

Question 23

Experimental evidence supporting LTP as a
memory mechanism

Answer 23

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

Question 24

what induces ltd

Answer 24

prolonged, low frequency stimulation

Question 25

what does ltd cause

Answer 25

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

Question 26

how do calcium dynamics lead to either LTP or LTD

Answer 26

* 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

Question 27

Hebb’s Postulate

Answer 27

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

Question 28

Long term plasticity

Answer 28

persistent changes in the strength of synaptic connectivity lasting hours, days, or longer

Question 29

hippocampus location and function

Answer 29

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

Question 30

NMDA receptor

Answer 30

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

Question 31

Long term potentiation

Answer 31

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)

Question 32

Late LTP

Answer 32

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

Question 33

Long term depression

Answer 33

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

Question 34

Calcium signaling

Answer 34

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)

Question 35

1. Describe how LTP is initiated and recorded in the hippocampus.

Question 36

2. 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.

Question 37

3. Explain how NMDA receptors act like coincidence detectors.

Question 38

4. Discuss how the same signal, Ca2+ entry through NMDA receptors, can trigger both LTD and LTP.

Question 39

5. Explain what aspects of LTP (or LTD) make it a promising substrate of learning and memory

Question 40

Experimental evidence supporting LTP as a memory mechanism.

Answer 40

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