A reduced number and function of synapses may underlie the smaller size and density of neurons in the dorsolateral prefrontal cortex (dlPFC) of patients with major depressive disorder (MDD). However, a direct causal relationship has not been demonstrated. Using microarray gene profiling and electron microscopic stereology, this study showed that patients with MDD have a reduced expression of various synapse-related genes and fewer synapses. Moreover, expression of the transcriptional repressor GATA1 is increased in dlPFC neurons of patients with MDD. In rats, Gata1 expression caused repression of these synaptic genes and loss of dendritic spines and dendrites, and induced depression-like behaviour. These data suggest that reversing dlPFC atrophy could be a strategy for treating depression.