NMDA receptor · Grey Matter

The NMDA receptor is the glutamate-gated ion channel that opens only when glutamate is bound and the membrane is already depolarised, and the calcium it then admits is the signal that starts most lasting changes in synaptic strength; it is the synapse's coincidence detector.

NMDA receptor. The NMDA receptor is the glutamate-gated ion channel that opens only when glutamate is bound and the membrane is already depolarised, and the calcium it then admits is the signal that starts most lasting changes in synaptic strength; it is the synapse's coincidence detector.

At resting voltage a magnesium ion from the extracellular fluid sits in the pore and blocks it, even with glutamate bound. Depolarisation (usually from the AMPA receptors beside it, or from a spike back-propagating into the dendrite) repels the magnesium, and the channel conducts sodium and, unusually, a substantial amount of calcium. Opening also requires a co-agonist, glycine or D-serine, bound at a second site. The receptor is slow: its current rises over several milliseconds and decays over about 50 to a few hundred milliseconds depending on its GluN2 subunits.

It reads two cells at once. Glutamate says the presynaptic cell has fired; the voltage says the postsynaptic cell is active. Only together do they let calcium in, which is the molecular form of the Hebbian rule.

The amount and timing of calcium decide the direction. A large, fast rise starts long-term potentiation; a modest, prolonged rise favours long-term depression.

Its slow current sums over time, helping dendrites integrate inputs and sustain activity in working-memory circuits.

Too much is toxic. Prolonged activation floods neurons with calcium, the core of excitotoxicity; ketamine and memantine block the open pore.

The NMDA receptor is a logical AND built into a channel.

Its magnesium plug turns the coincidence of input and output into a calcium signal, and that signal is where memory at the synapse begins.

Questions: How does too much glutamate kill a neuron? When glutamate stays high, its receptors stay open: sodium, chloride and water rush in and neurons swell within minutes, and calcium floods in through NMDA receptors and voltage-gated calcium channels. Experiments in cultured neurons showed that removing sodium prevents the swelling but the cells still die later unless calcium is removed too, so calcium is the lethal part. The excess calcium activates proteases and lipases, drives nitric oxide synthase, and overloads the mitochondria until they fail and release signals for cell death, producing reactive oxygen species on the way. Olney named the process excitotoxicity in 1969, and it is the shared final step of damage in stroke, trauma and prolonged seizures. How can nitric oxide signal without vesicles, receptors on the surface or a synapse? Nitric oxide is a small gas, so it is made at the moment it is needed and leaves the cell by diffusing straight through membranes. Its synthesising enzyme in neurons, nNOS, is activated by calcium and calmodulin and is often anchored next to NMDA receptors, so glutamate signalling that lets calcium in also makes nitric oxide. It spreads to nearby cells in all directions, including back to the presynaptic terminal, and acts on soluble guanylyl cyclase inside them, which makes the second messenger cyclic GMP. The signal cannot be aimed or stored, so it reports the level of local activity to everything within reach until it decays. How does calcium through NMDA receptors make a synapse stronger? Calcium entering a dendritic spine through NMDA receptors binds calmodulin, which activates the kinase CaMKII; CaMKII then phosphorylates its own neighbouring subunits and stays active after the calcium has gone. Active CaMKII phosphorylates AMPA receptors so that each one conducts more current, and helps capture additional AMPA receptors at the synapse, so the same release of glutamate produces a larger response. This early phase lasts an hour or so; keeping the change for days needs new proteins and growth of the spine. The direction depends on the calcium signal: a large, fast rise drives this potentiation, a modest, prolonged one drives depression instead. How does the NMDA receptor detect that two neurons fired together? The NMDA receptor needs two conditions at once: glutamate bound, which means the presynaptic cell has just released, and a depolarised membrane, which means the postsynaptic cell is active. At resting voltage a magnesium ion from outside the cell sits in the pore and blocks it even when glutamate is bound; depolarisation, usually from the AMPA receptors beside it or from a spike back-propagating into the dendrite, pushes the magnesium out. Only then does the channel pass current, including calcium. Glutamate alone opens just the AMPA receptors, depolarisation alone opens nothing, and the two together let in the calcium that signals plasticity. Why does the NMDA receptor need glycine as well as glutamate? The NMDA receptor is built from GluN1 subunits, which bind glycine (or D-serine), and GluN2 subunits, which bind glutamate, and the channel opens only when both sites are occupied. Johnson and Ascher showed in 1987 that glycine at low concentrations strongly increases NMDA responses, and later work found it to be required. The co-agonist site is a second key: glutamate signals the synapse's activity, and the level of glycine or D-serine, partly set by glial transporters and release, adjusts how readily NMDA receptors in a region can open. This glycine site is separate from the glycine receptor that inhibits spinal neurons, and it is insensitive to strychnine. Why does the order of two spikes, a few milliseconds apart, decide whether a synapse strengthens or weakens? In spike-timing-dependent plasticity, a presynaptic spike arriving a few milliseconds before the postsynaptic spike strengthens the synapse, and one arriving just after weakens it, within a window of about 20 ms on each side in Bi and Poo's hippocampal cultures. The NMDA receptor explains much of it: if glutamate binds first and the postsynaptic spike then back-propagates into the dendrite and expels the magnesium, a large burst of calcium enters, which favours potentiation. If the postsynaptic spike comes first, the depolarisation has passed by the time glutamate arrives, calcium entry is small, and depression follows. The rule rewards inputs that could have caused the spike and punishes those that came too late, a causal refinement of Hebb's idea.