Direct alteration of a specific inhibitory circuit of the hippocampus by antidepressants.

Correct brain functioning relies on the precise activity of a myriad of synapses assembling neurons in complex networks. In the hippocampus, highly diverse inhibitory circuits differently govern several physiologically relevant network activities. Particularly, perisomatic inhibition provided by specific interneurons was proposed to control emotional states, and could therefore be affected by mood disorders and their therapy. We found that both chronic and acute administration of two major antidepressants, imipramine and fluoxetine, strongly and directly altered GABA-mediated (GABAergic) hippocampal neurotransmission in mice and rats, independently of their effects on amine reuptake systems. These drugs affected GABA release from synapses formed by fast-spiking cells, but not interneurons expressing cannabinoid receptor type 1, resulting in the disruption of γ oscillations. This differential effect, shared by two types of antidepressants, suggests a new mechanism of action of these medications, and a possible role of perisomatic inhibition in depressive disorders.