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Mechanisms of Drug Action

Engaging homeostatic plasticity to treat depression

Abstract

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.

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Acknowledgements

This work was supported by an NIH-NIAAA pilot grant provided by the Integrated Neuroscience Initiative on Alcoholism (KRG), NSF grant IOS-1355158 (KRG) and Department of Defense USAMRMC Award W81XWH-14-10061 (KRG). We thank William Taylor for editing this manuscript. We thank Dr Fadel Zeidan for critical discussion and advice regarding human data and MDD.

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Workman, E., Niere, F. & Raab-Graham, K. Engaging homeostatic plasticity to treat depression. Mol Psychiatry 23, 26–35 (2018). https://doi.org/10.1038/mp.2017.225

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