Is subcortical–cortical midline activity in depression mediated by glutamate and GABA? A cross-species translational approach

Major depressive disorder has recently been characterized by abnormal resting state hyperactivity in anterior midline regions. The neurochemical mechanisms underlying resting state hyperactivity remain unclear. Since animal studies provide an opportunity to investigate subcortical regions and neurochemical mechanisms in more detail, we used a cross-species translational approach comparing a meta-analysis of human data to animal data on the functional anatomy and neurochemical modulation of resting state activity in depression. Animal and human data converged in showing resting state hyperactivity in various ventral midline regions. These were also characterized by abnormal concentrations of glutamate and γ-aminobutyric acid (GABA) as well as by NMDA receptor up-regulation and AMPA and GABA receptor down-regulation. This cross-species translational investigation suggests that resting state hyperactivity in depression occurs in subcortical and cortical midline regions and is mediated by glutamate and GABA metabolism. This provides insight into the biochemical underpinnings of resting state activity in both depressed and healthy subjects.