Schizophrenia: a genetic disorder of the synapse?

Glutamatergic synapses might be the site of primary abnormalities

Understanding the cause and pathogenesis of schizophrenia remains one of the great challenges in psychiatry. Progress has been slow, but one of the few certainties is that individual differences in liability are predominantly genetic.1 This information has, however, not been useful neurobiologically because the genes themselves had not been identified. This situation is beginning to change, allowing a reappraisal of existing hypotheses of pathogenesis.

Until recently the two leading hypotheses concerned dopamine and neurodevelopment. The classic dopamine hypothesis, which attributed schizophrenia to a hyperdopaminergic state, arose from the ability of dopaminergic drugs to induce a psychosis, and the realisation that the potency of antipsychotic drugs is proportional to their ability to block dopamine receptors.2 Refinements of the hypothesis indicate a more complex picture—increased dopaminergic transmission in the basal ganglia may underlie acute psychosis,3 but a prefrontal cortical …