A researcher applies low-frequency stimulation to a synapse and observes long-lasting synaptic weakening. Which chain of events best explains this LTD?
ALow stimulation reduces NMDA receptor number at the membrane, preventing calcium entry and weakening the synapse
BLow-frequency stimulation produces a modest calcium rise through NMDA receptors, activating phosphatases that remove AMPA receptors from the synapse
CLow stimulation activates a separate class of metabotropic receptors unrelated to LTP, triggering an independent weakening cascade
LTD at most excitatory synapses involves NMDA receptor-mediated calcium entry — the same receptors involved in LTP. The key is calcium quantity: low-frequency stimulation produces only a modest calcium rise, which preferentially activates phosphatases (calcineurin, PP1) rather than kinases. Phosphatases dephosphorylate AMPA receptors, triggering their internalization from the synapse membrane. With fewer AMPA receptors present, subsequent stimulation elicits a weaker postsynaptic response. The mechanism is postsynaptic, not presynaptic.
Question 2 Multiple Choice
Why would a nervous system capable only of LTP (synaptic strengthening) but never LTD eventually become dysfunctional?
ABecause LTP requires LTD to reset NMDA receptors between uses, so LTP itself would eventually fail
BBecause without LTD, all synapses would eventually saturate at maximum strength, eliminating the network's capacity to encode new distinctions between experiences
CBecause LTP is metabolically expensive and LTD provides the energy recovery needed to sustain further strengthening
DBecause LTD prevents excessive action potential firing that would otherwise cause seizures in all circuits
If synapses could only be strengthened, every synapse would eventually approach its maximum possible strength (maximum AMPA receptor density). At saturation, the network loses its dynamic range — it can no longer distinguish strong signals from weak ones, or encode new memories differentially. LTD provides the complementary 'write-down' operation that allows the system to weaken synaptic traces that are irrelevant or incorrect. This bidirectionality is what makes the system capable of storing a large number of distinguishable memories rather than a single maximally-activated state.
Question 3 True / False
The difference between LTP and LTD at the same synapse is primarily determined by the amount of calcium entering the postsynaptic cell, not by activation of different receptor types.
TTrue
FFalse
Answer: True
Both LTP and LTD are initiated through NMDA receptor activation and calcium influx. The calcium threshold model explains the bidirectionality: high-frequency stimulation drives large calcium spikes, which preferentially activate kinases (like CaMKII) that insert AMPA receptors (LTP). Low-frequency stimulation produces modest calcium rises that preferentially activate phosphatases that remove AMPA receptors (LTD). Same receptor, same ion, opposite outcomes — the difference is the calcium concentration and which downstream effectors that concentration recruits.
Question 4 True / False
LTD typically involves a decrease in presynaptic neurotransmitter release, which then reduces postsynaptic receptor activation.
TTrue
FFalse
Answer: False
Canonical NMDA-dependent LTD is a postsynaptic phenomenon: the presynaptic terminal continues releasing the same amount of neurotransmitter, but the postsynaptic response weakens because AMPA receptors are internalized from the synapse membrane. Fewer AMPA receptors means less depolarization for the same glutamate release. There are forms of presynaptic plasticity that alter neurotransmitter release, but the defining mechanism of NMDA-dependent LTD is postsynaptic AMPA receptor removal driven by modest calcium influx.
Question 5 Short Answer
Explain the calcium threshold model of synaptic plasticity and how it accounts for both LTP and LTD at the same synapse.
Think about your answer, then reveal below.
Model answer: The calcium threshold model proposes that the direction of synaptic change depends on the magnitude of calcium entry through NMDA receptors. High-frequency stimulation drives large calcium spikes that activate kinases (like CaMKII), which phosphorylate AMPA receptors and recruit additional ones to the synapse — producing LTP. Low-frequency stimulation produces only a modest calcium rise that preferentially activates phosphatases (calcineurin, PP1), which dephosphorylate AMPA receptors and trigger their internalization — producing LTD. Both outcomes use the same NMDA receptors and the same calcium ion; the calcium concentration determines which effector proteins are recruited and therefore whether the synapse strengthens or weakens.
The elegance of the calcium threshold model is that it explains bidirectional plasticity without requiring two entirely separate molecular pathways. The system is essentially a calcium sensor with two competing downstream signals: kinases win at high calcium, phosphatases win at low calcium. This makes the synapse sensitive to the pattern of activity — how often and how synchronously it is stimulated — rather than just whether it is stimulated at all. It is also the reason that timing matters so much for synaptic plasticity: the calcium concentration depends on how synchronized pre- and postsynaptic activity are.