Recent evidence indicates that glutamate homeostasis and neurotransmission are altered in major depressive disorder, but the nature of the disruption and the mechanisms by which it contributes to the syndrome are unclear. Glutamate can act via AMPA, NMDA, or metabotropic receptors. Using targeted mutagenesis, we demonstrate here that mice with deletion of the main AMPA receptor subunit GluR‐A represent a depression model with good face and construct validity, showing behavioral and neurochemical features of depression also postulated for human patients. GluR‐A^−/− mice display increased learned helplessness, decreased serotonin and norepinephrine levels, and disturbed glutamate ho‐meostasis with increased glutamate levels and increased NMDA receptor expression. These results correspond well with current concepts regarding the role of AMPA and NMDA receptors in depression, postulating that compounds that augment AMPA receptor signaling or decrease NMDA receptor functions have antidepressant effects. GluR‐A^−/− mice represent a model to investigate the pathophysiology underlying the depressive phenotype and to identify changes in neural plasticity and resilience evoked by the genetic alterations in glutamatergic function. Furthermore, GluR‐A^−/− mice may be a valuable tool to study biological mechanisms of AMPA receptor modulators and the efficacy of NMDA antagonists in reducing behavioral or biochemical changes that correlate with increased helplessness.—Chourbaji, S., Vogt, M. A., Fumagalli, F., Sohr, R., Frasca, A., Brandwein, C, Hörtnagl, H., Riva, M. A., Sprengel, R., Gass, P. AMPA receptor subunit 1 (GluR‐A) knockout mice model the glutamate hypothesis of depression. FASEB J. 22, 3129–3134 (2008)