Long Term Potentiation

What is LTP?

A form of activity dependent synaptic plasticity (strengthening of frequently used synapses which lasts a long time)

Likely to be a neural basis of learning and memory

What is the hippocampus important in?

Learning and memory

What is the trisynaptic pathway of the rat hippocampus?

Perforant path - neurons enter HP from entrorhinal cortex into dentate gyrus

Mossy fibre - from dentate gyrus to CA3

Schaffer-Collateral - from CA3 to CA1

Explain how each response occurs and forms the standard response

Upon stimulation of the schaffer-collateral (input) glutamate is released onto the AMPA receptors on the CA1 dendritic spine causing a fast EPSP

CA1 activation sends a feedback signal to a GABAergic neuron which synapses back onto the CA1 soma releasing GABA which binds GABA A receptors causing a fast IPSP

The schaffer-collateral neuron has a collateral axon which synapses and activates a GABAergic interneuron, providing feed forward inhibition which synapses onto the CA1 dendritic spine releasing GABA which acts on GABA B receptors causing a slow IPSP

The schaffer-collateral glutamate also binds on to NMDA receptors however since NMDA produces a slower response the cell is not depolarised long enough to overcome the Mg block as GABAergic IPSPs hyperpolarise the cell

Explain the induction of LTP with the images L → R then below

1. Typical response after a low frequency stimulation

2. If a high frequency stimulation protocol (10-100Hz) the EPSPs overcome the GABAergic inhibition (feed forward and back) and therefore can depolarise the cell enough to repel the Mg block in NMDA receptors allowing Ca to enter into cells

   (occurs randomly in vivo obvs)

3. Upon returning to a low frequency protocol the EPSP amplitude is increased suggesting the synapse was strengthened by the HF stim protocol

4. Baseline recordings made over 30mins at low frequency stimulation provides a baseline amplitude

   After a HF protocol there is a dramatic increase in EPSP amplitude which decreases upon returning to low frequency however it remains elevate than before for more than 120mins (further studies show perisitent change for 1yr+)

Describe the mechanism of LTP induction

At low frequency stim glutamte binds AMPA and NMDA where AMPA opens and Na floods in (little K out) but NMDA is blocked by Mg

High frequency stimulation allows lots of Na to enter via AMPA receptors (as lots of glut released) which depolarises the cell sufficently to repel the Mg out of NMDA receptor channel allowing Ca entry

Upon returning to low frequency stimulation the Mg block recurrs however when AMPA is activated the EPSP amplitude is larger

How is the increase in EPSP amplitude thought to occur through?

Increased conductance - changes in the properties of the ion channel causing an increased permability to sodium

Increased no. of AMPA receptors - receptor no is dynamic as receptors arenconstantly inserted and recycled and replaced but after the HF stim there are more AMPA receptors inserted/less recycled causing a net increase in AMPA receptors

What evidence is there to prove NMDA is involved in LTP induction?

Addition of AP5 (NMDA antagonist) blocks induction of LTP after a high frequency stimulation - while there is an intial increase in EPSP amplitude, it quickly returns to basline after

AP5 also has no effect on the control (baseline) or potentiated response (doesn’t cause return to baseline)

Postsynaptic EGTA (Ca chelator with higher affinity for Ca than EDTA which has affinity for Ca and Mg) blocks induction of LTP - proof Ca is involved (NMDA receptors undergo Ca switch)

Postsynaptic hyperpolarisation blocks induction of LTP as the cell does not depolarise sufficently to remove Mg block

What does it mean that LTP is SPECIFIC?

LTP is specific only to frequently used synapses, synapses receiveing the HF stimulation

Other synapses on the same neuron, same dendritic spine do not undergo LTP when a neigboruing synapse gets a HF protocol

What does it mean that LTP requires COOPERATIVITY?

When a SC is stimulated at a low frequency AND the postsynaptic CA1 is injected with a positive current (enough to remove Mg block) LTP still occurs (in absence of HF stimulation) however it takes longer 5-10mins instead of 1s

This shows synchrony in pre and post firing is crucial which is termed the ‘Hebbian‘ property (cells which fire together wire together)

This dubs NMDA a molecular coincidence detector

What evidence linke LTP to learning and memory?

Hippocampal lesions impair learning and memory (patient HM)

Occlusion experiments show that consistent HF stim should saturate synapse and prevent further memories forming however we can never confirm saturation of synapse (like solar eclipse the sun is blocked but still there, LTP occurs but is blocked)

Describe how the Morris Water Maze is used to asses the formation of spatial memory and prove NMDA is key in that memory formation through LTP

1. A mouse is placed in a deep cloudy pool with landmarks surrounding the pool

   The mouse will swim around randomly and eventually it will find a hidden platform to stand on

   This experiment is repeated multiple times (months-days) and eventually the animal will use the landmarks to quickly locate the platform

2. Suddenly the platform will be removed and the time spent in each quadrant will be measured

   Can see that the animal speand majority of the time in the correct quadrant = spatial memory reserved

   If D-AP5 is infused into the ventricles near the hippocampus to block NMDA and LTP the animal spends equal time in each quadrant - no spatial memory

   If L-AP5, an enantiomer which doesn’t bind NMDA, is infused it has no effect and the animal spends the most time in the correct quadrant = LTP and spatial memory intact