Questions: NMDA Receptors and Ca2+-Dependent Signaling in Synaptic Plasticity

Question 1

A presynaptic neuron fires and releases glutamate onto a postsynaptic neuron that is at resting membrane potential (−70 mV). What happens at the synapse?

• A. Both AMPA and NMDA receptors open, Ca²⁺ enters the cell, and LTP is induced
• B. AMPA receptors open and produce a small depolarization, but NMDA receptors remain blocked by Mg²⁺ — no Ca²⁺ enters and no LTP is triggered
• C. NMDA receptors open immediately upon glutamate binding regardless of membrane voltage, but LTP requires repeated activation
• D. Neither receptor opens at resting potential; glutamate alone is insufficient without a co-agonist released from the postsynaptic cell

Answer: (B)

At resting membrane potential, a Mg²⁺ ion sits in the NMDA receptor pore and blocks ion flow even when glutamate is bound. AMPA receptors have no such voltage dependence and open normally, producing an EPSP. The Mg²⁺ block is only relieved when the postsynaptic membrane depolarizes to roughly −40 mV or above — at which point electrostatic repulsion expels the Mg²⁺. Without this depolarization, the NMDA receptor is sealed regardless of how much glutamate is present, so no Ca²⁺ enters and no LTP occurs.

Question 2

What makes the NMDA receptor a 'molecular coincidence detector' for Hebbian learning?

• A. It binds both glutamate and GABA, detecting convergent excitatory and inhibitory signals from multiple presynaptic neurons
• B. It requires both glutamate binding (signaling presynaptic activity) and postsynaptic depolarization (signaling postsynaptic activity) simultaneously — the channel opens only when both conditions are met
• C. It activates only when the postsynaptic neuron has already fired an action potential within the preceding 100 milliseconds
• D. It detects coincident Ca²⁺ and Na⁺ influx from neighboring synapses on the same dendritic branch

Answer: (B)

The Mg²⁺ block is the physical mechanism of coincidence detection. Glutamate is the 'presynaptic signal' (the pre-neuron fired). Postsynaptic depolarization is the 'postsynaptic signal' (the post-neuron is active). Only when both are present simultaneously does the Mg²⁺ leave the pore and Ca²⁺ flow in. This directly implements Hebb's rule: 'neurons that fire together wire together.' A presynaptic neuron firing onto a quiet postsynaptic neuron leaves no lasting trace; a synapse active when the postsynaptic cell is already depolarized gets strengthened.

Question 3

NMDA receptor-mediated Ca²⁺ influx is necessary for LTP because Ca²⁺ activates CaMKII, which drives insertion of additional AMPA receptors into the postsynaptic membrane.

• T. True
• F. False

Answer: True

This is the established molecular sequence for LTP induction. Ca²⁺ entering through NMDA receptors binds calmodulin, which activates CaMKII (calcium/calmodulin-dependent protein kinase II). CaMKII phosphorylates existing AMPA receptors, increasing their conductance, and also signals for the insertion of new AMPA receptors from intracellular stores into the postsynaptic membrane. The net result is more AMPA receptors at the synapse, producing a larger EPSP in response to the same presynaptic release — this is LTP. Blocking NMDA receptors (e.g., with AP5) prevents LTP.

Question 4

NMDA receptors are blocked by Mg²⁺ mainly at strongly depolarized membrane potentials; at resting potential they are freely permeable to Ca²⁺ whenever glutamate is bound.

• T. True
• F. False

Answer: False

This is exactly backwards. At resting membrane potential (around −70 mV), Mg²⁺ sits in the pore and blocks ion flow. The block is *relieved* at depolarized potentials (above roughly −40 mV), where the positive membrane potential pushes the positively charged Mg²⁺ out of the pore. So NMDA receptors are open at depolarized potentials and blocked at rest. This counterintuitive feature — a channel that opens when the membrane is depolarized rather than closing — is what makes NMDA receptors useful as coincidence detectors.

Question 5

Explain why long-term potentiation (LTP) is input-specific: why does strong activation of one synapse onto a neuron strengthen that synapse but not neighboring synapses on the same dendrite?

Model answer: LTP is input-specific because NMDA receptors only open at synapses where both glutamate and local postsynaptic depolarization are present simultaneously. At an inactive synapse on the same neuron, no glutamate is released, so even if the postsynaptic cell is depolarized, there is no glutamate to bind the NMDA receptors — they stay shut. No Ca²⁺ enters, no CaMKII is activated, and no AMPA receptors are added. Only the specific active synapse, where both conditions coincide, receives the Ca²⁺ signal that drives potentiation.

This input-specificity is what makes LTP a plausible mechanism for associative memory — it can strengthen a specific pathway without indiscriminately boosting all synaptic connections onto a neuron. The NMDA receptor's requirement for local glutamate (not just global depolarization) confines the plasticity signal to the synapse where presynaptic and postsynaptic activity converged. This is the molecular implementation of the Hebbian learning rule at the synapse-specific level.