L2: Synaptic plasticity

Long term depression and synaptic tag hypothesis

For synapses to be plastic there needs to be…

1. poteniation

And

2. Depression

Why is this?

• allows more flexible neuronal network

• If synaptic plasticity only enhances synaptic connection→ synaptic efficacy would everntually saturate

  • THEREFORE: depression mechanisms are also required

One protocol to induce long term depression in hippocampal Schaffer collaterals-CA1 connection

• Low frequency stimulation

• (in contrast to high frequency stimulation that induce NMDAR LTP)

But what does ‘low’ frequenecy actually mean?

• Still higher than the baseline synaptic transmission

  • just lower than the high stimulation

Numbers of frequencies for baseline and LTD

• Baseline→ frequnecy of 0.1Hz→ one stimulation of presynaptic neuron e.g Schaffer collaterals per second)

• For LTD→ 1 Hz→ for a total of 900 stimuli

  • although can be higher

Following induction, stimulation frequency is decreased back to…

• Baseline 0.1 Hz

Different frequencies that can be used as ‘low frequency’ LTD protocol (put in graphs here)

1. 1Hz

2. 3Hz

3. 10Hz→ no depression is induced→ slope of EPSP increases back to baseline level→ following an initial drop

4. 50Hz→ induced LTP

THEREFORE→ there is a frequency threshold for LTD and LTP generation

• graph shows that is is around 10Hz

Both LTD induction and high freqency LTP induction in the CA1 region of the hippocampus are…

• NMDAR dependent

• but if they both depend on the same mechanism of Ca2+ entry through NMDARs→ how does frequency of stimulation translate to LTD or LTP??

How does low frequency cause LTD and not LTP, using NMDARs?

1. low freuency stimulation→ increases Calcium entry via NMDARs

2. BUT→ extent of calcium elevation is lower than for LTP induction with HFS

3. Therefore: different cellular mechanism

   1. lower Caclium entry activates certain phosphatase

   2. this is because they have a higher affinity for Ca2+ than the CamKII from LTP did

   3. result in endocytosis of AMPARS from postsynaptic site

4. Decreasing the EPSP

5. Decrease in AMPAR levels is the expression of low frequnecy LTD

   1. opposite of expression of NMDAR-dependent LTP→ where there was increase in AMPAR component

Looking back at LTP protocols→ NMDAR-dependent LTP protocol result in…

• potentiation of synaptic transmission

  • → for up to an hour

  • THEREFORE: EARLY LTP 

Why referred to as early LTP?

• one hour post induction→ synaptic strength goes back to what it was at baseline levels

What is late LTP

• when potentiation of synaptic strength persists

  • for several hours

How is late LTP caused?

• increasing the number of HFS protocols applied:

  1. larger and more rapid increase in Ca2+ entry in the post-synaptic cell

  2. activates protein kinase A (and CamKII) 

  3. translocates to the soma and then nucleus

  4. activates transciption factor Cyclic AMP Response Element-Binding protein  (CREB)

  5. Binds to cAMP response elements (CRE) 

     • in regulatory region of target genes to initiate their transcription

  6. mRNA transcripts transported

     • into proteins in the cell body

     • or transported along with translated proteins to dendrite for translation

What genes are upregulated

• over 80 genes potentially upregulated

• as a result of Late LTP

What is the overall effect of these genes/proteins?

• maintain the increase in AMPAR expression

• for a longer period

As there are many dendrties distally and proximally to the soma→

• how do these mRNA transcripts and newly translated proteins locate the dendritic spine that that LTP was induced in?

Importance of this

• LTP is input specific

• mRNA transcripts are proteins need to find their way to location where early LTP  was induced 

• so they can maintain it to the late LTP phase

• and not translocate to a spine where no LTP was induced

must be something to do with early LTP?

Hypothesis→ Synaptic Flag Hypothesis

1. unknown tag/flag is only present following early LTP induction

2. tag/flag draws the mRNA and proteins to that specific location

What is this flag?

1. Actin?

2. Actin binding proteins?

Why thought to be actin/actin binding proteins

During early LTP we get an increase in both

1. AMPAR expression

2. size of the spine→→ this growth is supposed by an increase in actin cytoskeleton

What does this growth of spine cause?

• attract new mRNA transcipts and proteins

• to the location of the enlaged spine

When does the spine and actin cytoskeleon enlargement occur?

• during early phase of LTP

• hypothetically→ provides the expression of the tag

Late LTP also requires…

1. Protein kinase A translocation

and

2. gene transciption

Evidence for this:

Experiment:

• When first induced late LTP via 10 x HFS protocol in one pathway

• After 1 hours→ induced only early LTP in a different pathway via 1xHFS protocol:

Result→ early LTP was converted to late LTP

Why is this?

• The flag was expressed by 1xHFS protocol but not→gene transcription

however

• the new mRNA transcripts and proteins are provided by the first 10xHFS stimulated pathway

• THEREFORE: as the second pathway has the flag available

  • the mRNA transcripts and proteins can also translocate to tis dendrite 

  • → maintain the LTP to a later phase