Locally Dynamic Synaptic learning rules in pyramidal neuron dendrites

What does “synapse-specific LTP” mean?

Only the stimulated synapse undergoes potentiation, meaning each synapse can act as an independent learning unit.

What is heterosynaptic spread of LTP?

When LTP at one synapse also affects or “spreads” to neighboring synapses nearby on the dendrite, reducing their independence.

What does heterosynaptic metaplasticity predict?

LTP at one group of synapses makes it harder (raises the threshold) for nearby synapses to undergo LTP.

What does clustered plasticity predict?

LTP at one spine makes it easier (lowers the threshold) for nearby spines to undergo LTP, possibly through local tagging mechanisms.

What was the main experimental goal of this study?

To test whether LTP in one synapse makes nearby synapses:

• Harder to potentiate (metaplasticity), or

• Easier to potentiate (clustered plasticity).

What happens when they stimulated Spine 1 with a strong stimulus and a neighbouring spine with a weak stimulus

They held the neuron at 0MV to remove the Mg block + uncaging and stimulated the spine (protocol pairing) to induce a strong LTP, then they applied a weak stimulus (usually too weak to cause LTP) in the neighbouring spine which also undergoes FULL LTP because the first spine’s potentiation lowered the threshold for the neighbouring spine

What happened when they held the cell at -70mV and what did this indicate

At -70mV, the LTP protocol LTP failed to LTP in either the stimulated spine or its neighbor. This meant that crosstalk requires actual LTP induction via NMDA receptor mediated Ca influx, not just the uncaging procedure

In the uncaging only experiment (no depolarization, Mg removed), what happened when one spine received strong stimulation and a neighbouring spine later received subthreshold stimulation?

The first spine showed full, long lasting LTP, and the neighbouring spine also underwent full, persistent LTP, just as strong as the LTP spine 

This showed that LTP and crosstalk can occur with just NMDAr Ca entry, without artifical depolarization. Meaning clustered plasticity is a realistic natural mechanism

In this paper, how did they prove that crosstalk happens under physiological (normal conditions)

They stimulated schaffer collatetral cells which mimics what would actually happen in the brain

This triggered LTP and volume increase. Two minutes later a subthreshold stimulus (usually too weak to cause LTP) was applied to the neighbouring spine which caused a full, persisten LTP

Proving that crosstalk can occur in natural conditions

What is STDP (Spike-timing-dependent-plasticity)

A plasticity rule where the itming between an EPSP and a postsynaptic AP determines LTP. 

• If the time between EPSP and postsynaptic AP = tens of ms = LTP

• If the time between EPSP and postynaptic AP = 30-40 ms = No LTP

What happens in normal STDP at single spines

At Δt = 5 ms, spines show strong LTP

At Δt = 35 ms, no LTP occurs

How does crosstalk affect STDP 

After one spine undergoes LTP with Δt = 5 ms, a nearby spine can also now undergo full LTP even with Δt = 35ms

Meaning crosstalk broadens the STDP window and lower the threshold for potentiation at neighbouring spine 

What are the time and distance limits of crosstalk between spines?

Crosstalk lasts about 10 mins and spreads only 8-10um along the SAME dendritic branch. Beyond this time or distance, subthrehold inputs no longer induce LTP

Is crosstalk mediated by extracellular or intracellular factors? How was this tested?

It requires intracellular signaling spread. When two spines were close in space BUT on DIFFERENT dendritic branches = no cross talk

Meaning crosstalk depended on intracellular factors like calcium ions, kinases, and second messenger

Does crosstalk rely on Ca release from intracellular stores?

No. Blocking ER Ca release with thapsigargin and ryanodine had no effect, showing crosstalk does not depend on intracellular Ca stores

(remember, Ca entry through NMDAr is still needed)

Compare and contrast order of weak and strong stimulus for crosstalk and synaptic tagging

Crosstalk = order matters = strong LTP first, then weak

Synaptic tagging = works in both orders → weak can come before or after a strong stimulus because tagged synapses can capture proteins later

Compare and contrast synaptic tagging and crosstalk in terms of protein synthesis

Corsstalk does NOT require new protein synthesis - LTP still happens when protein synthesis inhibitors are applied 

Synaptic tagging = needs protein synthesis because weakly stimulated synapses depend on capturing plasticity related proteins (PRPs) 

How is crosstalk different from synaptic tagging

Crosstalk is order dependent | Tagging isnt order dependent 

Crosstalk doesnt depend on PRPs | Tagging depends on PRPs 

Crosstalk is short lived | Tagging lasts for hours

After blocking multiple mechanisms (CPP, Thaps + ryanodine, and anisomycin) what did they conclude about how these affected crosstalk 

• CPP (NMDAR blocker): Completely blocked crosstalk  -> shows NMDAR calcium entry is required 

• Thap + ryanodine (blocks Ca release from internal stores): no effect -> intracellular stores are not required 

• Anisomycin (protein synthesis inhbitor): No effect -> protein synthesis is not required 

How does corsstalk contribute to memory storage?

Crosstalk lowers the threshold for LTP in nearby spines, crosstalk allows clusters of synapses on the same dendritic branch to potentiate together

This binding of related inputs creates coherent memory traces (engrams) and icnreases learning efficiency

What does crosstalk imply for plasticity models

Synapses arent fully independent, instead, groups of 10-20 spines on the same dendritic branch can act together. This supports clustered plasticity models where spines in the same area store memory traces

How does Calcium signals digger between stimulates spines, subthreshold spines, and neighbouring spines

Stmulated = large Ca influx

Stimulated neighbouring spines: Smaller Ca influx, not enough for LTP

Unstimulated spines: No Ca signal