CA3-CA1 Synaptic Plasticity 2

Question 1

The problem with having only LTP as a synaptic mechanism underlying memory

Answer 1

If synaptic weights can only be increased:

• then eventually all synapses would become fully potentiated
• as the synaptic weights increased to a ceiling point where no further increase in synaptic efficacy could occur.

Question 2

How could the hippocampal system maintain flexibility?

Answer 2

Through the dissociation and reassociation of synaptic connectivity particularly in the hippocampus once short memories have been consolidated in the neocortex as long-term ones

Question 3

CA3-CA1 LTD experiment

Answer 3

Initially, monitor baseline transmission at <0.1Hz
Induction protocol: 1Hz for 15 minutes (900 stimuli) - low frequency stimulation (LFS)
After 15 minutes return to baseline transmission frequency.
Sustained depression of synaptic responses to about 80% of control level >60 min.
Input specific & homosynaptic
Extracellular recordings from stratum radiatum (dendritic layers) of CA1

Question 4

CA3-CA1 LTD depends on…

Answer 4

…NMDA-R activation, postsynaptic membrane potential depolarisation, increase in postsynaptic intracellular Ca2+

Question 5

CA3-CA1 LTD vs LTP

Answer 5

Consider the difference between the induction protocol - frequency
900 stimuli at 1-50Hz.
• Freq >10Hz → LTP.
• Freq <10Hz → LTD.
Threshold level of postsynaptic activation required for LTP, otherwise there is LTD.
Both LTP and LTD blocked by AP5 (both NMDA-dependent), and require depolarization and Ca2+ entry.
Suggests plasticity change is determined by the degree to which presynaptic activity affects postsynaptic neurones

Question 6

During LFS…

Answer 6

…correlated pre and postsynaptic activation, but

this leads to depression or a decrease in synaptic weight.

Question 7

CA1 hippocampal synapses can…

Answer 7

…exhibit changes in weight in a Hebbian manner when there is an increase and i n an anti-Hebbian meanner when there is as decrease

Question 8

CA3-CA1 LTD expression blocked by

Answer 8

Okadaic acid - ser/thr protein phosphatase 1 and 2A (PP1 & PP2A) inhibitor.
FK506 - calcineurin (ser/thr protein phosphatase 2B or PP2B) inhibitor.
But not protein kinase inhibitors!!!!

Question 9

LTD induction protocols lead to…

Answer 9

…dephosphorylation of S845 on the GluR1 subunit of AMPA receptors

Question 10

Phosphorylation of S845 leads to…

Answer 10

…decreased open time probability; initiates retrieval of AMPAR from
synaptic membrane by endocytosis (reverse of priming insertion)

Question 11

CA3-CA1 LTD v LTP threshold: activation of protein phosphatases v kinase

Answer 11

Both LTP and LTD involve activation of calmodulin (via binding of Ca2+)
Intracellular postsynaptic [Ca2+] determines whether LTP or LTD is induced.
>5μM → LTP (phosphorylation). <1μM → LTD (dephosphorylation).

Question 12

Bidirectional model for AMPA-R phosphorylation

Answer 12

Low [Ca2+]i –> ­ dephosphorylation of CaMKII and AMPA receptors.
High [Ca2+]i –> ­ phosphorylation of CaMKII and AMPA receptors.
Two phosphorylation sites on AMPA receptor GluR1 subunit at Ser831 and Ser845 determine the state of the macroscopic conductance of the EPSC

Question 13

Three relatively rapid postsynaptic changes occuring during the early phase of LTP/D (first two hours)

Answer 13

• phosphorylation/dephosphorylation of AMPA receptors
• insertion/removal of AMPA receptors
• increase/(decrease?) in the number of synaptic contacts

Question 14

Following the early phase of LTP/D…

Answer 14

…there are both presynaptic and postsynaptic re-modeling to re-enforce these changes and help maintain the late phase of LTP/LTD - synaptogenesis/synaptic pruning.

Question 15

Five fundamental properties of a memory mechanism (Morris)

Answer 15

1) Be present in areas vital for memory.
2 Work quickly to encode memories.
3) Produce changes that last a long time (LTM).
4) Exhibit specificity. Only those synapses that form the memory should be affected.
5) Be associative.

Question 16

Does LTP meet Morris’ fundamental requirements for a memory mechanism?

Answer 16

1) Yes; seen in the hippocampus, cortex, amygdala, etc.
2) Yes; induction <1 minute.
3) Yes; can last for weeks in vivo.
4) Yes; neighbouring unstimulated synapses are not potentiated.
5) Yes; occurs when multiple inputs drive postsynaptic activation.