Engaging homeostatic plasticity to treat depression

Mol Psychiatry. 2018 Jan;23(1):26-35. doi: 10.1038/mp.2017.225. Epub 2017 Nov 14.


Major depressive disorder (MDD) is a complex and heterogeneous mood disorder, making it difficult to develop a generalized, pharmacological therapy that is effective for all who suffer from MDD. Through the fortuitous discovery of N-methyl-D-aspartate receptor (NMDAR) antagonists as effective antidepressants, we have gained key insights into how antidepressant effects can be produced at the circuit and molecular levels. NMDAR antagonists act as rapid-acting antidepressants such that relief from depressive symptoms occurs within hours of a single injection. The mode of action of NMDAR antagonists seemingly relies on their ability to activate protein-synthesis-dependent homeostatic mechanisms that restore top-down excitatory connections. Recent evidence suggests that NMDAR antagonists relieve depressive symptoms by forming new synapses resulting in increased excitatory drive. This event requires the mammalian target of rapamycin complex 1 (mTORC1), a signaling pathway that regulates synaptic protein synthesis. Herein, we review critical studies that shed light on the action of NMDAR antagonists as rapid-acting antidepressants and how they engage a neuron's or neural network's homeostatic mechanisms to self-correct. Recent studies notably demonstrate that a shift in γ-amino-butyric acid receptor B (GABABR) function, from inhibitory to excitatory, is required for mTORC1-dependent translation with NMDAR antagonists. Finally, we discuss how GABABR activation of mTORC1 helps resolve key discrepancies between rapid-acting antidepressants and local homeostatic mechanisms.

Publication types

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

MeSH terms

  • Animals
  • Antidepressive Agents / therapeutic use
  • Depressive Disorder, Major / pathology*
  • Depressive Disorder, Major / physiopathology*
  • Depressive Disorder, Major / therapy
  • GABA Agents / pharmacology
  • GABA Agents / therapeutic use
  • Homeostasis / drug effects
  • Homeostasis / physiology*
  • Humans
  • Models, Molecular
  • Neuronal Plasticity / drug effects
  • Neuronal Plasticity / physiology*
  • Receptors, GABA / metabolism
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / metabolism


  • Antidepressive Agents
  • GABA Agents
  • Receptors, GABA
  • Receptors, N-Methyl-D-Aspartate