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Neuroscientist. 2009 Oct;15(5):525-39. doi: 10.1177/1073858409336093. Epub 2009 May 26.

The role of the tripartite glutamatergic synapse in the pathophysiology and therapeutics of mood disorders.

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  • 1Experimental Therapeutics, Mood and Anxiety Disorders Research Program, NIMH-NIH, Bethesda, Maryland 20892, USA.

Erratum in

  • Neuroscientist. 2010 Apr;16(2):199.


Bipolar disorder and major depressive disorder are common, chronic, and recurrent mood disorders that affect the lives of millions of individuals worldwide. Growing evidence suggests that glutamatergic system dysfunction is directly involved in mood disorders. This article describes the role of the "tripartite glutamatergic synapse," comprising presynaptic and postsynaptic neurons and glial cells, in the pathophysiology and therapeutics of mood disorders. Glutamatergic neurons and glia directly control synaptic and extrasynaptic glutamate levels/ release through integrative effects that target glutamate excitatory amino acid transporters, postsynaptic density proteins, ionotropic receptors (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid [AMPA], N-methyl-D-aspartate [NMDA], and kainate), and metabotropic receptors. This article also explores the glutamatergic modulators riluzole and ketamine, which are considered valuable proof-of-concept agents for developing the next generation of antidepressants and mood stabilizers. In therapeutically relevant paradigms, ketamine preferentially targets postsynaptic AMPA/NMDA receptors, and riluzole preferentially targets presynaptic voltage-operated channels and glia.

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