Long-term potentiation (LTP) at hippocampal Schaffer collateral synapses requires NMDA receptor activation. The molecular 'coincidence detector' function of the NMDA receptor requires:

• A Sequential AMPA then NMDA receptor activation over repeated stimuli regardless of membrane potential
• B Simultaneous binding of glutamate (ligand) AND membrane depolarization to relieve Mg2+ block; when both conditions are met, Ca2+ influx triggers LTP via CaMKII autophosphorylation ✓
• C GABA co-release with glutamate to activate NMDA receptors which require inhibitory co-agonists
• D cAMP elevation by adenylyl cyclase which phosphorylates NMDA channel directly to open it

Explanation

NMDA receptors function as molecular coincidence detectors because they require two simultaneous conditions for activation: (1) Glutamate binding (presynaptic requirement) and (2) Postsynaptic membrane depolarization to relieve voltage-dependent Mg2+ block of the channel pore (postsynaptic requirement—Hebbian requirement). At resting membrane potential, Mg2+ physically blocks the NMDA channel even when glutamate is bound; depolarization (usually by AMPA receptor activation during repeated or strong stimulation) expels the Mg2+. Ca2+ then flows in through activated NMDA channels, binding calmodulin, activating CaMKII (Ca2+/calmodulin-dependent protein kinase II). CaMKII autophosphorylates, becoming constitutively active, and phosphorylates AMPA receptors (increasing conductance) and promotes additional AMPA receptor insertion into the synapse—the synaptic strengthening of LTP. This molecular mechanism implements Hebb's rule ('fire together, wire together').

Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.

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