Questions: Synaptic Plasticity: Long-Term Potentiation and Depression

Question 1

A researcher blocks all AMPA receptors in a postsynaptic neuron and then delivers high-frequency presynaptic stimulation. What happens to LTP induction?

• A. LTP occurs normally because NMDA receptors can detect presynaptic activity independently
• B. LTP is blocked because AMPA-mediated depolarization is required to relieve the Mg²⁺ block on NMDA receptors
• C. LTP is enhanced because there is no competition for AMPA receptor insertion sites
• D. LTP is replaced by LTD because the postsynaptic membrane stays hyperpolarized

Answer: (B)

The NMDA receptor is a coincidence detector: it requires both glutamate binding AND postsynaptic depolarization to open. The Mg²⁺ block is only relieved when the postsynaptic membrane is already depolarized — normally achieved by AMPA receptor activation. With AMPA receptors blocked, the membrane stays near resting potential, the Mg²⁺ block persists, Ca²⁺ cannot enter through NMDA receptors, and LTP cannot be induced. Option A is the classic misconception — as if the NMDA receptor responds to presynaptic activity alone.

Question 2

After LTP is established at a synapse, NMDA receptor antagonists are applied. What effect does this have on the potentiated synaptic response?

• A. The potentiated response decays back to baseline because NMDA receptors are required to maintain LTP
• B. The potentiated response is preserved because LTP expression depends on inserted AMPA receptors, not ongoing NMDA activity
• C. The potentiated response is enhanced because NMDA blockade prevents any further LTD
• D. The potentiated response fluctuates unpredictably without NMDA receptor input

Answer: (B)

LTP induction requires NMDA-mediated Ca²⁺ influx to activate kinases and insert AMPA receptors. But LTP expression — the maintained increase in synaptic strength — depends on the extra AMPA receptors now in the membrane, not on continued NMDA activity. Blocking NMDA receptors after LTP is established does not remove the AMPA receptors, so the potentiated response persists. Induction and expression are mechanistically distinct.

Question 3

The NMDA receptor acts as a molecular coincidence detector because it requires both presynaptic glutamate release and postsynaptic membrane depolarization to open.

• T. True
• F. False

Answer: True

This is the defining property of the NMDA receptor that enables associative learning. At resting potential, a Mg²⁺ ion physically blocks the channel even when glutamate is bound. The block is only relieved when the postsynaptic membrane is already depolarized (typically by AMPA receptor activation). Both conditions must be met simultaneously — 'coincidence detection' — and it is this requirement that makes the NMDA receptor the molecular substrate for Hebbian learning: only synapses whose presynaptic activity correlates with postsynaptic firing get strengthened.

Question 4

Long-term depression (LTD) uses a largely different receptor and ion channel than LTP, which is why weak stimulation produces the opposite outcome.

• T. True
• F. False

Answer: False

LTD and LTP both depend on the NMDA receptor and Ca²⁺ influx — the same receptor and the same ion. What differs is the amplitude and kinetics of the Ca²⁺ signal. High-frequency or coincident stimulation produces a large, rapid Ca²⁺ rise that activates kinases (particularly CaMKII), leading to AMPA receptor phosphorylation and insertion (LTP). Weak or asynchronous stimulation produces a smaller, slower Ca²⁺ signal that preferentially activates phosphatases, leading to AMPA receptor dephosphorylation and internalization (LTD). Same receptor, same ion, opposite outcomes — determined by the pattern of activity.

Question 5

Why does the direction of synaptic change — potentiation versus depression — depend on the pattern of Ca²⁺ influx rather than simply on whether Ca²⁺ enters the postsynaptic cell?

Model answer: The amplitude and kinetics of Ca²⁺ influx determine which downstream enzymes are activated. A large, rapid Ca²⁺ rise (from high-frequency or coincident stimulation) preferentially activates kinases like CaMKII, which phosphorylate and insert AMPA receptors, potentiating the synapse. A small, slow Ca²⁺ rise (from weak or asynchronous stimulation) preferentially activates phosphatases, which dephosphorylate and internalize AMPA receptors, depressing the synapse. The threshold and kinetics differ for the two enzyme classes, making the Ca²⁺ signal a graded switch.

This is the key insight: Ca²⁺ is not just an on/off signal but a graded, temporally-patterned signal. Kinases have a higher activation threshold than phosphatases, so only the large Ca²⁺ signal triggers potentiation. The same molecular machinery reads the quantitative properties of Ca²⁺ entry and routes the outcome in opposite directions — a single ion species acting as a bidirectional plasticity switch depending on how it enters.