Major depressive disorder (MDD) is a highly disabling psychiatric syndrome affecting many aspects of behavior and cognitive functions, including memory. MDD is strongly associated with stress and with deficits in specific subpopulations of GABAergic interneurons. However, the underlying molecular mechanisms linking these observations are not fully understood. The activity-regulated gene Arc/Arg3.1 is rapidly up-regulated by acquiring novel experience, learning and memory, and synaptic plasticity-inducing stimuli1,2. Acute stress has also been reported to elevate the levels of Arc/Arg3.1 mRNA or protein3. Here, we investigated Arc/Arg3.1 expression in inhibitory neurons and its contribution to stress-mediated and MDD-like behaviors in mice. We show that acute stress upregulates Arc/Arg3.1 in specific populations of GABAergic inhibitory neurons. Genetic deletion of Arc/Arg3.1 in these neurons, but not in others, induced depression-like behaviors in a number of benchmark tests of MDD. Our results reveal a novel role of Arc/Arg3.1 in distinct and specific subpopulations of inhibitory neurons, which could link GABAergic plasticity to MDD. Linke et al. J Comp Neurol. 1995; 351: 602-616. doi: 10.1002/cne.903140102Plath, O. Ohana et al. Neuron. 2006.52(3): 437-444. doi: 10.1016/j.neuron.2006.08.024Mikkelsen and Larsen. Neurosci Lett. 2006; 403(3):239-243. doi: 10.1016/j.neulet.2006.04.040