Questions: NMDA Receptors: Structure and Properties

Question 1

A presynaptic neuron fires weakly, releasing a small amount of glutamate onto a postsynaptic cell that is near its resting membrane potential (around −65 mV). What happens to NMDA receptor current at that synapse?

• A. NMDA receptors open fully because glutamate is the only requirement for gating
• B. NMDA receptors open partially, passing a small calcium current proportional to the amount of glutamate
• C. NMDA receptors remain blocked by Mg²⁺ and pass little or no current, even though glutamate is bound
• D. NMDA receptors open but pass only sodium, not calcium, at resting potential

Answer: (C)

At resting potential (−65 mV), a Mg²⁺ ion sits in the NMDA receptor channel pore and blocks ion flow even when glutamate is bound. Glutamate binding alone is necessary but not sufficient — the postsynaptic membrane must also be depolarized to expel the Mg²⁺ block by electrostatic repulsion. Weak presynaptic activity produces little AMPA-mediated depolarization, so the Mg²⁺ block persists and NMDAR current is minimal. This is the mechanistic basis of the coincidence detection property.

Question 2

Why does NMDA receptor opening require postsynaptic depolarization in addition to glutamate binding?

• A. Glutamate binds to both GluN1 and GluN2 subunits, and GluN2 only changes conformation when the membrane is depolarized
• B. A Mg²⁺ ion physically blocks the open pore at resting membrane potential; depolarization electrostatically expels it, allowing ion flow
• C. Depolarization causes conformational changes in the channel that increase its affinity for glutamate
• D. NMDA receptors require voltage-gated calcium channels to open first, which then depolarize the membrane to activate the NMDAR

Answer: (B)

The Mg²⁺ block is the mechanism. At resting potential, a divalent Mg²⁺ ion sits in the channel pore, blocking it despite glutamate being bound. When the membrane depolarizes — typically because nearby AMPA receptors have been activated — the reduced electronegativity inside the cell no longer holds the Mg²⁺ in the pore, and it is expelled. Now, with both glutamate bound AND the pore unblocked, current (including Ca²⁺) flows through the NMDAR. This voltage-dependent gating by a blocking ion is unusual among ligand-gated channels and is what makes NMDARs coincidence detectors.

Question 3

NMDA receptor opening requires simultaneous glutamate binding and postsynaptic membrane depolarization, making the receptor sensitive to the correlation between pre- and postsynaptic activity.

• T. True
• F. False

Answer: True

This is the core property of NMDARs. The glutamate requirement reflects presynaptic activity; the depolarization requirement reflects postsynaptic activity (typically driven by prior AMPA receptor activation). Both conditions must be met simultaneously for the channel to open. This coincidence detection is the molecular implementation of Hebb's rule — the NMDAR opens only when pre- and postsynaptic neurons are both active at the same time, triggering the calcium influx that drives synaptic plasticity.

Question 4

NMDA receptors open faster than AMPA receptors and produce larger, more rapid excitatory currents in response to glutamate.

• T. True
• F. False

Answer: False

This is the opposite of reality. NMDARs have notably slow kinetics compared to AMPA receptors — they open slowly and remain open longer. AMPA receptors generate the fast component of the excitatory postsynaptic potential. NMDARs contribute little to fast signaling but provide the slow, sustained calcium entry that triggers plasticity. The slow timecourse of NMDAR activation is part of why they serve an integrative function rather than a fast signal-relay function.

Question 5

Explain why the Mg²⁺ block makes NMDA receptors act as coincidence detectors, and why this property matters for learning.

Model answer: The Mg²⁺ ion blocks the NMDAR pore at resting membrane potential. Glutamate binding alone (presynaptic signal) is insufficient to open it. The membrane must also be depolarized (postsynaptic signal), which happens when nearby AMPA receptors have been activated by strong or repeated stimulation. Thus the NMDAR only opens when presynaptic activity (glutamate release) and postsynaptic activity (depolarization) occur simultaneously. This coincidence condition means NMDARs detect correlated activity between two neurons — the exact condition Hebb's rule specifies for strengthening synaptic connections. When NMDARs do open, the resulting Ca²⁺ influx triggers the signaling cascades that long-term potentiation.

The Mg²⁺ block is the physical implementation of logical AND: both conditions (glutamate AND depolarization) must be true simultaneously for the channel to open. This is why NMDARs are called coincidence detectors and why disrupting NMDAR function impairs learning and memory — without coincidence detection, the synapse cannot distinguish correlated from uncorrelated activity and cannot selectively strengthen the right connections.