Glutamate and GABA: The Brain's Accelerator and Brake

The two most abundant transmitters in the brain — glutamate exciting, GABA inhibiting — how their balance keeps the brain stable, and what alcohol, anaesthetics, sedatives and seizures have to do with it.

If you could count every synapse in the cerebral cortex, the great majority would use one of two molecules: glutamate or GABA.

Glutamate: the accelerator

Glutamate is an amino acid, also found in food (it gives savoury umami taste — the "G" in MSG is glutamate, though dietary glutamate doesn't freely reach the brain). In the brain it is the main excitatory transmitter, used by pyramidal neurons in the cortex and hippocampus and by most long-range connections. It acts on fast AMPA and NMDA receptors and on slower metabotropic receptors. The NMDA receptor is central to learning: its calcium signal triggers long-term potentiation.

Glutamate has a dark side. Excess glutamate overstimulates neurons, letting in so much calcium that it kills them — excitotoxicity. This contributes to brain damage after stroke and head injury. Astrocytes guard against it by rapidly pumping glutamate away.

GABA: the brake

GABA (gamma-aminobutyric acid) is made from glutamate by a single enzyme. It is the main inhibitory transmitter in the brain, used mostly by local interneurons. GABA-A receptors let negatively charged chloride ions in, holding neurons below threshold; GABA-B receptors act more slowly via G proteins. Inhibitory interneurons shape the timing of brain activity and generate rhythms such as gamma oscillations.

Many drugs boost GABA-A receptors: benzodiazepines (such as diazepam), barbiturates, some general anaesthetics, and alcohol. That's why they cause sedation, reduce anxiety and are dangerous in combination. In the developing brain, GABA can actually be excitatory, because immature neurons hold more chloride inside.

Balance

The excitation–inhibition balance keeps the brain responsive but stable. Tip it toward excitation and you risk seizures — many anti-seizure drugs boost GABA or damp glutamate. Imbalances are also being studied in autism, schizophrenia and anxiety. Ketamine, which blocks NMDA receptors, is used as an anaesthetic and, in lower doses, as a fast-acting treatment for depression.