Abstract
What changes in brain function cause the debilitating symptoms of depression? Can we use the answers to this question to invent more effective, faster acting antidepressant drug therapies? This review provides an overview and update of the converging human and preclinical evidence supporting the hypothesis that changes in the function of excitatory synapses impair the function of the circuits they are embedded in to give rise to the pathological changes in mood, hedonic state, and thought processes that characterize depression. The review also highlights complementary human and preclinical findings that classical and novel antidepressant drugs relieve the symptoms of depression by restoring the functions of these same synapses and circuits. These findings offer a useful path forward for designing better antidepressant compounds.