GABA & Glutamate

The excitation/inhibition balance — the ratio of glutamatergic drive to GABAergic inhibition — is fundamental to the proper functioning of every neural circuit. When E/I balance is disrupted, the consequences depend on direction and location. Insufficient inhibition (too much E relative to I) in sensory cortex may produce sensory hypersensitivity, as proposed in autism spectrum disorder; in hippocampus it can produce seizure activity; in prefrontal circuits it may generate the disorganised thinking of psychosis. Excessive inhibition relative to excitation can impair working memory, reduce learning, and produce sedation. Many psychiatric conditions — schizophrenia, autism, anxiety disorders, PTSD — are increasingly conceptualised as E/I imbalances in specific circuits rather than simply as disorders of a single neurotransmitter.

The glutamate hypothesis proposes that hypofunction of NMDA receptors is central to the pathophysiology of schizophrenia. The key evidence is that NMDA receptor antagonists — phencyclidine (PCP) and ketamine — produce in healthy individuals a syndrome closely resembling schizophrenia, including positive symptoms (hallucinations, delusions), negative symptoms (blunting, withdrawal), and cognitive impairments. This drug model reproduces the full range of schizophrenia symptoms more faithfully than dopamine agonists, which primarily produce positive symptoms. The hypothesis proposes that NMDA hypofunction on GABAergic interneurons in the prefrontal cortex disinhibits pyramidal neurons, leading secondarily to dysregulated dopamine release in limbic areas — potentially reconciling the glutamate and dopamine hypotheses.

Benzodiazepines enhance GABAergic inhibition by increasing the frequency of GABA-A chloride channel opening. With repeated use, the brain compensates by reducing the number and sensitivity of GABA-A receptors — a form of tolerance. When benzodiazepines are withdrawn, GABAergic inhibition falls below normal levels, producing a rebound in excitability: anxiety, insomnia, tremor, and in severe cases, seizures. This is the physiological basis of benzodiazepine dependence. The severity of withdrawal reflects both the duration of use and the half-life of the specific benzodiazepine. Gradual dose reduction, rather than abrupt cessation, is standard clinical practice.

Long-term potentiation (LTP) is a persistent increase in synaptic strength between two neurons that is produced by their repeated co-activation. First described in the hippocampus by Bliss and Lømo (1973), it provides a candidate cellular mechanism for the formation of long-term memories — embodying Hebb's postulate that 'neurons that fire together, wire together'. LTP is NMDA receptor-dependent: the NMDA receptor's requirement for simultaneous pre- and postsynaptic activity makes it a Hebbian coincidence detector. The psychological relevance is that any drug, disease, or genetic variation affecting NMDA receptor function will in principle affect memory formation — explaining why NMDA antagonists produce amnesia, and why deficits in synaptic plasticity are implicated in cognitive disorders.