If GABA is the brake, glutamate is the accelerator. It is the dominant excitatory neurotransmitter in the central nervous system, and the great majority of fast point-to-point signaling between neurons uses it. Where GABA whispers not yet, glutamate says now, and harder.
Glutamate has several receptors, but the one to memorize is NMDA. It is named after a synthetic agonist, N-methyl-D-aspartate, but what makes it interesting is not the chemistry; it is the behavior. The NMDA receptor is a coincidence detector. It opens only when two things happen at once: glutamate binds, and the receiving neuron is already depolarized. Either alone does nothing. Both together open the channel.
When the channel opens, calcium flows in. Calcium is a second messenger that triggers a cascade of changes inside the neuron — receptor trafficking, structural remodeling of the synapse, gene expression. The net effect is that the synapse becomes stronger. The next time this same pair of neurons fires together, the postsynaptic neuron responds more easily. This is long-term potentiation, and it is the cellular substrate of learning and memory.
Hebb's old slogan — neurons that fire together wire together — describes this mechanism. The NMDA receptor is the molecular implementation of that rule. It is the gate that writes memory.
Now the paradox. Ketamine is an NMDA antagonist. It blocks the gate. You would think blocking the receptor that writes memory would impair cognition broadly, and at sufficient doses it does — that is how ketamine works as a dissociative anesthetic. But at sub-anesthetic doses, ketamine produces a rapid antidepressant effect. Within hours, not weeks. In patients who have failed multiple SSRIs.
The mechanism is still being worked out, but the leading hypothesis is that brief NMDA antagonism produces a paradoxical glutamate surge after the drug wears off, which triggers a burst of synaptic remodeling in mood-regulating circuits. Block the gate briefly; the system re-tunes. This finding reopened a field that had been static for decades, because every other antidepressant we know works at monoamine targets and takes weeks. Ketamine, esketamine, and the next generation of NMDA-modulating drugs work somewhere else, and they work fast.
Hold the picture. Glutamate is the accelerator. NMDA is the gate that writes memory. And blocking it briefly, in carefully chosen patients, lifts depression in a way that takes monoamine drugs two months to approach.