Neuroplasticity part 2 - Spike timing dependant plasticity

Spike timing dependant plasticity:

However it has become apparent that the neuroplasticity may be more complicated than Hebbian plasticity. In particular timing plays a very important role.

This new form of plasticity is called spike timing dependant plasticity (STDP)

Language of STDP

Action potentials in the presynaptic cell cause synaptic potentials in the post synaptic cells.

These can be excitatory or inhibitory:

·         Excitatory post synaptic potential – EPSP

·         Inhibitory post synaptic potential – IPSP

Usually a single synapse induces a sub-threshold potential,

When many (hundreds) combine they cause a depolarisation.

• Strengthening of a synapse is known as:  - Long term potentiation

The EPSP evoked by the presynaptic cell on that synapse will be greater. This is what we mean by increasing the synaptic strength. LTP increases the EPSP. This potentiation only occurs at those synapses which where stimulated.

• The weakening of synaptic strengths is known as -  Long term depression.

The EPSP will be smaller, This is what we mean when we say a synapse is weakened. LTD decreases the EPSP

Temporal specificity:

What determines whether a synapse will undergo LTP or LTD? it’s all a matter of timing.

• If the presynaptic neurone fires before the post synaptic neurone within the preceding 20ms – long term potentiation occurs.

• If the presynaptic neurone fires after the post synaptic neurone, within the following 20ms  – Long term depression occurs.

There is a critical window for synaptic plasticity, with the peak time for changes to synaptic strengths being in 20 seconds before and after an action potential.

We can then alter the initial Hebbian hypothesis to include the new findings;

If the presynaptic neurone fires within a window of 20ms before the postsynaptic window the synapse will be strengthened (LTP), however if the presynaptic neurone fires within a window of 20ms after the postsynaptic neurone, the synapse will be weakened.

Associativity:

Although the key time window for effective synaptic modification is 20ms, in certain circumstances the window can be increased to up to 40 milliseconds.

This is due to associativity.

Some weak synaptic inputs that cause only small EPSPs will not lead to LTP,

However if these arrive close in time to a larger input, both these synapses will show LTP.

This means that weak inputs that are not normally able to modify synapses, do cause synaptic strengthening if associated with another strong input.

This is what is meant by associativity

Cellular mechanism of neuroplasticity:

The cellular mechanism can vary depending in which area of the brain the memory is stored and which type of memory is being encoded. The classic and most widely studied type is that in the hippocampus and is thought to the basis for long-term memory, which we will discuss now.

Glutamate receptors:

Glutamate is released from the presynaptic neurone.

Glutamate activates glutamate receptors.

There are two particularly important glutamate receptors,

• AMPA receptor
• NDMA receptor

The AMPA receptor is permeable to K⁺ and Na⁺ and it is this inward flux through the AMPA receptor which depolarises the cell.

The NDMA receptors in contrast are blocked by magnesium at negative voltages, and therefore do not significantly contribute to the postsynaptic depolarisation of the cell. However once the cell is depolarised the magnesium is displaced, and ions then flow through the NDMA receptor. Importantly the NDMA receptor also allows calcium to flow through.

It is the nature of the calcium current which causes Spike timing dependant plasticity.

Calcium current and timing:

If the presynaptic neurone fires first:

It becomes depolarised and release glutamate

The glutamate binds to AMPA receptors causing it to depolarise,

At the same time it and binds NDMA receptors,

as the cell is depolarised it causes a large calcium influx.

If the post synaptic neurone fires first.

It becomes depolarised.

As it is repolarising the presynaptic neurone fires, and releases glutamate.

 glutamate binds to the NDMA receptors, but Because the cell is repolarising it is at a lower voltage,

This means fewer NDMA can open.

This leads to a more moderate calcium influx.

• A large calcium influx leads to LTP
• A small calcium influx leads to LTD

Recycling of AMPA receptors:

In the cell, AMPA receptors are constantly being recycled.

New ones are undergoing exocytosis onto the perisynaptic sites where they then migrate the post synaptic areas. Receptors at the post synaptic areas are migrating to perisynaptic sites where they undergo endocytosis and are brought back into the cell.

Endosomes inside the post synaptic neurone are thought to contain a pool of AMPA receptors.

A large calcium influx increases the number of AMPA receptors:

A calcium influx large enough to cross a critical threshold will activate calcium dependant kinases, most importantly CaMKII.

These kinases alter the recycling of AMPA receptors, in particular they increase the exocytosis of them.

This increases the number of AMPA receptors on the post synaptic terminal.

They also change the structure of the AMPA receptors to make them more permeable.

This means when this synapse is triggered again, more AMPA receptors are there to open, more current flows through and the EPSP is increased.

A small calcium influx decreases the number of AMPA receptors

A more moderate calcium influx does not cross the critical threshold to activate calcium dependant kinases, and instead it only activates protein phosphatases.

These again alter the recycling of AMPA receptors, but in the opposite way.

They increase the endocytosis of AMPA receptors, decreasing the number of them at the post synaptic terminal.

Phosphatases, also de phosphorylate receptors and make them less permeable.

This means when the synapse is triggered again, fewer receptors are there to open, less current flows through and the EPSP is decreased.

In Summary. the plasticity is our brain is all due to the timing of synaptic potentials.

is the pre synaptic neurone fires before the post synaptic neurone, the synapse will be strengthened

if the post synaptic neurone fires before the pre synaptic neurone, the synapse will be weakened.

This all due to the nature of the calcium influx, a large influx increases the number of AMPA receptors, leading to LTP and a small influx decreases the number of AMPA receptors, leading to LTP.

How the brain manages such temporal precision will become apparent in the next entry, on neuronal oscillations.

Sources:

Mu-ming Poo Part 1: The Cellular Basis of Learning and Memory. http://www.ibioseminars.org

Hebb, D.O. (1949). The organization of behaviour. New York: Wiley & Sons

Postsynaptic protein phosphorylation and LTP. Soderling TR, Derkach VA. Trends Neurosci. 2000 Feb;23(2):75-80.

Synaptic Plasticity: Multiple Forms, Functions, and Mechanisms. Ami Citri. Robert C Malenka. Neuropsychopharmacology (2008) 33, 18–41

Paul C. Bressloff, lectures in mathematical neuroscience http://www.neurosecurity.com/articles/PCMI/Lect5.pdf

(date accessed 28/10/2012)

Note:

It is important to note that the neuroplasticity coverd here is that of STDP in the hippocampus. But there are other types of synaptic plasticity, acting with different mechanism and at different timescales, to perform different functions. The nature of neuroplasticity itself is very plastic! a phenomena known as metaplasticity.