GAD₆₇: the link between the GABA-deficit hypothesis and the dopaminergic- and glutamatergic theories of psychosis

Summary.

Decreases in the 67 kDa isoenzyme of brain glutamic acid decarboxylase (GAD₆₇) expression have been consistently found in patients with bipolar disorder and schizophrenia. In animals GAD₆₇ expression is diminished by chronic, but not acute stimulation of dopamine D₂ receptors and by short-term blockade of NMDA receptors. In contrast, chronic treatment with D₂ receptor antagonists enhances GAD₆₇ expression. Thus, antipsychotic treatment cannot explain the reduction in GAD₆₇ levels in patients with psychotic disorders. Rather, pathophysiological findings such as reduced viability of cortical glutamatergic neurones (in schizophrenia) or enhanced dopamine sensitivity (in bipolar disorder) might explain the observed reduction in GAD₆₇. Since reduction in GAD₆₇ expression leads to reduced levels of GABA, the GABAergic inhibitory control over glutamatergic cells is reduced. Psychosis could result from AMPA receptor activation caused by overactivity of the glutamatergic system. GAD₆₇ levels would thus be a surrogate marker for psychosis liability. Pharmacological principles that raise GAD₆₇ expression levels could represent novel targets for antipsychotic therapy.