- Excitation/inhibition (E/I) balance
- The dynamic equilibrium between excitatory (primarily glutamatergic) and inhibitory (primarily GABAergic) synaptic inputs in a neural circuit. Healthy brain function requires E/I balance to be maintained within a narrow operating range: too much excitation leads to seizures, hyperarousal, and excitotoxicity; too little inhibition produces anxiety, sensory hypersensitivity, and disinhibited cognition. Disruption of E/I balance — either local or network-level — has been implicated in epilepsy, autism spectrum disorder, schizophrenia, and anxiety disorders.
- NMDA receptor
- A subtype of ionotropic glutamate receptor with unique coincidence-detection properties: it requires simultaneous ligand binding (glutamate + the co-agonist glycine or D-serine) AND membrane depolarisation to relieve a magnesium block on the channel. When both conditions are met, calcium floods into the postsynaptic neuron, triggering the signalling cascades that underlie long-term potentiation (LTP). This molecular coincidence detection makes the NMDA receptor the leading candidate mechanism for Hebbian 'fire together, wire together' plasticity. NMDA receptor hypofunction — produced by antagonists like ketamine or phencyclidine — generates psychotic symptoms and cognitive impairments resembling schizophrenia, driving the glutamate hypothesis.
- Long-term potentiation (LTP)
- A persistent strengthening of a synapse following brief, high-frequency stimulation, lasting from hours to potentially days or longer. First described by Bliss and Lømo (1973) in the hippocampus, LTP is NMDA-receptor-dependent at most synapses: calcium entry through activated NMDA receptors triggers phosphorylation and trafficking of additional AMPA receptors to the postsynaptic membrane, increasing the synapse's sensitivity to future glutamate release. LTP is the most widely studied candidate cellular mechanism for memory formation and is considered a key form of synaptic plasticity.
- GABA-A receptor and benzodiazepines
- GABA-A is an ionotropic receptor — a pentameric chloride channel that opens when GABA binds, hyperpolarising the neuron and reducing its excitability. It has multiple distinct binding sites: the GABA site (orthosteric), a benzodiazepine site (allosteric), a barbiturate site, and an alcohol site. Benzodiazepines (diazepam, lorazepam) bind the allosteric site and increase the frequency with which the chloride channel opens in response to GABA — amplifying inhibitory tone without directly opening channels. This explains their anxiolytic, sedative, anticonvulsant, and muscle-relaxant effects, and also their potential for tolerance and dependence with chronic use.
- Excitotoxicity
- Neuronal death caused by excessive activation of glutamate receptors, particularly NMDA receptors, leading to pathological calcium influx. Calcium overload overwhelms mitochondrial function, activates destructive enzymes (proteases, phospholipases, endonucleases), and triggers apoptosis or necrosis. Excitotoxicity is a principal mechanism of neuronal death in ischaemic stroke (where energy failure allows glutamate to accumulate), traumatic brain injury, and status epilepticus. The concept was developed primarily by John Olney, who coined the term in 1969.