Questions: Synaptic Plasticity Mechanisms

Question 1

The NMDA receptor is called a 'coincidence detector.' In the context of LTP induction, what two conditions must coincide for Ca2+ to flow through it?

• A. Glutamate binding and glycine co-agonist binding at two separate sites on the receptor
• B. Glutamate release from the presynaptic terminal AND sufficient depolarization of the postsynaptic membrane to relieve the Mg2+ block
• C. High-frequency stimulation of the presynaptic terminal AND activation of neighboring inhibitory interneurons
• D. Simultaneous opening of NMDA receptors at two adjacent synapses on the same dendritic branch

Answer: (B)

The Mg2+ block is the key: at resting potential the pore is physically plugged by Mg2+, so even with glutamate bound no current flows. The block is only relieved when the postsynaptic membrane depolarizes — typically because AMPA receptors at the same synapse are already open and passing current. Ca2+ then flows only when glutamate is present (presynaptic activity) AND the postsynaptic cell is already depolarized. This dual requirement is exactly Hebb's rule implemented molecularly.

Question 2

After LTP is induced at a synapse, the EPSP in response to the same glutamate input is significantly larger. The primary cellular mechanism underlying this increase is:

• A. Increased neurotransmitter release from the presynaptic terminal due to calcium-dependent facilitation
• B. Insertion of additional AMPA receptors into the postsynaptic membrane, increasing current flow for the same glutamate stimulus
• C. Upregulation of NMDA receptor expression, increasing calcium entry on subsequent stimulations
• D. Retraction of neighboring inhibitory synapses, reducing competition for postsynaptic current

Answer: (B)

LTP works primarily by increasing postsynaptic AMPA receptor number. Ca2+ entering through NMDA receptors activates CaMKII, which phosphorylates existing AMPA receptors (making them conduct more) and signals for additional AMPA receptors to be trafficked from intracellular stores to the membrane. More AMPA receptors mean a larger EPSP to the same glutamate input — the synapse is 'stronger.' This is why blocking AMPA trafficking blocks LTP even when NMDA receptors are intact.

Question 3

LTD (long-term depression) and LTP (long-term potentiation) are inverse processes that use the same kinase machinery in reverse — AMPA receptors are removed by the same CaMKII that inserts them during LTP.

• T. True
• F. False

Answer: False

LTP and LTD are not mirror processes and do not use the same enzymes. LTP requires large Ca2+ influx that activates kinases (especially CaMKII), leading to AMPA receptor insertion. LTD requires a smaller, more modest Ca2+ rise that instead activates phosphatases, leading to AMPA receptor removal and internalization. Different Ca2+ magnitudes activate entirely different downstream enzymes. The magnitude of the Ca2+ signal — not just its presence — determines the direction of plasticity.

Question 4

Protein synthesis inhibitors block long-term memory consolidation without affecting short-term memory because only the late phase of LTP requires new protein synthesis.

• T. True
• F. False

Answer: True

Early-phase LTP (hours) is achieved through post-translational modification: phosphorylation of existing AMPA receptors and receptor trafficking from internal pools. These processes do not require new protein synthesis. Late-phase LTP (days or longer) requires gene transcription and translation of new structural proteins for dendritic spine growth and synaptic remodeling. Protein synthesis inhibitors block this late phase while leaving early-phase LTP intact — directly explaining the dissociation between short-term and long-term memory in behavioral experiments.

Question 5

Explain how the NMDA receptor implements Hebb's rule ('neurons that fire together, wire together') at the molecular level.

Model answer: The NMDA receptor physically detects the co-occurrence of presynaptic and postsynaptic activity. Its pore is blocked by Mg2+ at resting potential, preventing Ca2+ entry even when glutamate is bound. The Mg2+ block is relieved only when the postsynaptic membrane is sufficiently depolarized — which happens when the postsynaptic cell is already active (via AMPA receptor activation at the same synapse). So Ca2+ flows only when both presynaptic glutamate release AND postsynaptic depolarization coincide. That Ca2+ influx then activates CaMKII, driving AMPA receptor insertion and synapse strengthening.

Hebb's rule is not just a metaphor — it has a direct molecular implementation. The NMDA receptor acts as a molecular 'AND gate,' requiring both inputs simultaneously. Presynaptic firing alone (glutamate present, but postsynaptic cell at rest — Mg2+ block intact) produces no Ca2+ and no LTP. Postsynaptic depolarization alone (no glutamate, so NMDA receptors not bound) also fails. Only coincident activity — the precise Hebbian condition — opens the gate. The NMDA receptor thus translates correlation between pre- and postsynaptic firing into a biochemical signal that physically strengthens the connection.