A synapse receives high-frequency stimulation, producing large, rapid calcium transients. Another synapse receives low-frequency stimulation (1 Hz for several minutes), producing a moderate, sustained calcium elevation. What determines which synapse undergoes LTP vs LTD?
AThe type of receptor activated — AMPA receptors drive LTP while NMDA receptors drive LTD
BWhether calcium enters at all — LTP requires calcium but LTD does not
CThe amount and pattern of calcium elevation — high transients activate kinases (LTP) while moderate sustained elevation activates phosphatases (LTD)
DThe direction of the change — LTP is always initiated by the presynaptic cell while LTD requires a postsynaptic signal
The BCM threshold model: both LTP and LTD are triggered by calcium entering through NMDA receptors, but the amount of calcium determines the outcome. Large, rapid calcium transients from high-frequency stimulation activate CaMKII and other kinases, inserting AMPA receptors and strengthening the synapse (LTP). Moderate, sustained calcium from low-frequency stimulation activates calcineurin and PP1 (phosphatases), removing AMPA receptors and weakening the synapse (LTD). The calcium signal itself encodes the plasticity direction.
Question 2 Multiple Choice
If calcineurin activity is pharmacologically blocked during low-frequency stimulation, what would you expect to observe?
AEnhanced LTD — removing calcineurin allows other phosphatases to act more strongly
BLTP instead of LTD — kinases now dominate unopposed
CLTD is prevented or reduced — AMPA receptor internalization requires calcineurin-mediated dephosphorylation
DNo change — calcineurin is not involved in synaptic plasticity
Calcineurin (protein phosphatase 2B) is a key enzyme that, when activated by moderate calcium, dephosphorylates proteins that normally anchor AMPA receptors at the postsynaptic membrane. This triggers endocytosis of AMPA receptors — the mechanistic basis of LTD. Blocking calcineurin prevents this dephosphorylation step, so AMPA receptors remain at the synapse and LTD is impaired. This pharmacological approach has been used experimentally to confirm calcineurin's causal role.
Question 3 True / False
LTD and LTP both require calcium entry through NMDA receptors, but they differ in the amount and pattern of calcium elevation produced.
TTrue
FFalse
Answer: True
True. This is the central insight of the BCM model of bidirectional synaptic plasticity. NMDA receptors act as the common gateway for both processes, but the downstream signaling diverges based on calcium amplitude and timing. High, brief calcium → kinase pathway → LTP. Low, sustained calcium → phosphatase pathway → LTD. The same receptor mediates opposite outcomes depending on the pattern of activation — a feature of enormous computational power.
Question 4 True / False
LTD weakens synapses by reducing glutamate release from the presynaptic terminal.
TTrue
FFalse
Answer: False
LTD is primarily a postsynaptic phenomenon. The weakening occurs through AMPA receptor internalization (endocytosis) at the postsynaptic membrane — fewer receptors means smaller electrical responses to the same amount of glutamate. Glutamate release from the presynaptic terminal is not reduced. This distinction matters: LTD changes the postsynaptic sensitivity to neurotransmitter, not the amount of neurotransmitter released. (Some presynaptic forms of LTD do exist, particularly at specific synapses, but the canonical NMDA-dependent cerebellar and hippocampal LTD is postsynaptic.)
Question 5 Short Answer
Explain why a brain that could only undergo LTP — but not LTD — would have severely impaired learning ability.
Think about your answer, then reveal below.
Model answer: Without LTD, synaptic strength can only increase. Over time, all synapses would approach maximum strength (saturation), making it impossible to encode new information — every input would produce the same maximal response, destroying the signal-to-noise ratio that allows discrimination between patterns. LTD provides the erasure and pruning that keeps synaptic weights in a dynamic range. In the cerebellum, LTD is the mechanism for correcting motor errors. In the hippocampus, it allows old associations to be overwritten. Without LTD, the network becomes a one-way ratchet: good at remembering early experiences, unable to adapt.
This tests whether students grasp LTD's functional role, not just its mechanism. The point is that strengthening and weakening are equally necessary for computation — a synapse scale with only one direction is useless for storing variable information.