Stimulation of entorhinal cortex-dentate gyrus circuitry is antidepressive

Nat Med. 2018 May;24(5):658-666. doi: 10.1038/s41591-018-0002-1. Epub 2018 Apr 16.


Major depressive disorder (MDD) is considered a 'circuitopathy', and brain stimulation therapies hold promise for ameliorating MDD symptoms, including hippocampal dysfunction. It is unknown whether stimulation of upstream hippocampal circuitry, such as the entorhinal cortex (Ent), is antidepressive, although Ent stimulation improves learning and memory in mice and humans. Here we show that molecular targeting (Ent-specific knockdown of a psychosocial stress-induced protein) and chemogenetic stimulation of Ent neurons induce antidepressive-like effects in mice. Mechanistically, we show that Ent-stimulation-induced antidepressive-like behavior relies on the generation of new hippocampal neurons. Thus, controlled stimulation of Ent hippocampal afferents is antidepressive via increased hippocampal neurogenesis. These findings emphasize the power and potential of Ent glutamatergic afferent stimulation-previously well-known for its ability to influence learning and memory-for MDD treatment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antidepressive Agents / therapeutic use*
  • Behavior, Animal
  • Chronic Disease
  • Dendrites / pathology
  • Dentate Gyrus / pathology*
  • Entorhinal Cortex / pathology*
  • Glutamates / metabolism
  • HEK293 Cells
  • Humans
  • Membrane Proteins / deficiency
  • Membrane Proteins / metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nerve Net / metabolism
  • Nerve Net / pathology
  • Neurogenesis
  • Peroxins / deficiency
  • Peroxins / metabolism
  • Stress, Psychological / complications


  • Antidepressive Agents
  • Glutamates
  • Membrane Proteins
  • Peroxins
  • Pex5l protein, mouse