Excitatory synapses in the brain, which use glutamate as the primary neurotransmitter, represent a crucial target for the action of stress and its mediators. Mounting evidence suggests that stress, along with the associated hormonal and neurochemical mediators (particularly glucocorticoids), induces changes in glutamate release, transmission and metabolism in cortical and limbic brain areas, thereby influencing cognitive and emotional processing and behaviour.
Depending on age, gender, duration and the type of the stressors experienced, stress may either have beneficial effects on cognitive and emotional functions or induce noxious and maladaptive changes in brain tissue, which have been linked to the development of neuropsychiatric disorders.
Acute stress enhances glutamatergic synaptic transmission in the prefrontal cortex and other limbic regions, thereby facilitating certain cognitive functions.
Acute stress increases glutamate release, membrane trafficking of AMPA and NMDA receptors, and potentially glutamate clearance in the prefrontal cortex through various mechanisms that involve glucocorticoid regulation.
Chronic stress has been associated with a loss of glutamate receptors, impaired glutamate cycling and a suppression of glutamate transmission that may be attributable to the observed impairment of prefrontal cortex-dependent cognitive functions.
These findings suggest that a new line of drug development aimed at minimizing the effects of chronic stress exposure on the function of the glutamatergic neurotransmitter system may prove beneficial in clinical settings. Straightforward pharmacological intervention on different regulatory sites of the glutamate synapse is a possible strategy for bypassing the unmet therapeutic needs posed by traditional drugs based on monoaminergic mechanisms.
Mounting evidence suggests that acute and chronic stress, especially the stress-induced release of glucocorticoids, induces changes in glutamate neurotransmission in the prefrontal cortex and the hippocampus, thereby influencing some aspects of cognitive processing. In addition, dysfunction of glutamatergic neurotransmission is increasingly considered to be a core feature of stress-related mental illnesses. Recent studies have shed light on the mechanisms by which stress and glucocorticoids affect glutamate transmission, including effects on glutamate release, glutamate receptors and glutamate clearance and metabolism. This new understanding provides insights into normal brain functioning, as well as the pathophysiology and potential new treatments of stress-related neuropsychiatric disorders.
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M.P. is supported by the Italian Ministry of University and Research (MIUR-PRIN), the National Alliance for Research on Schizophrenia and Depression (NARSAD) and the European Union (FP6 — GENDEP Project). Z.Y. is supported by grants MH85774 and MH84233 from the US National Institute of Mental Health (NIMH). B.S.M. is supported by grant MH41256 from the NIMH, Conte Center grant 5 P50 MH58911 to J. Ledoux (principal investigator at New York University), and the MacArthur Foundation Research Network on Socioeconomic Status and Health. G.S. is supported by grants R01 MH081211 and 5 R01 MH071676-05 from the NIMH, the NARSAD, the National Center for Posttraumatic Stress Disorder of the US Department of Veterans Affairs, and the Clinical Neuroscience Division (West Haven, Connecticut) of the Department of Mental Health and Addiction Services for the State of Connecticut.
M.P. received support and/or has consulted for Abiogen, GlaxoSmithKline, MerckSharp and Dohme, Servier and Fidia. G.S. has received consulting fees from AstraZeneca, Avanier Pharmaceuticals, Bristol-Myers Squibb, Evotec, Eli Lilly & Co., Hoffman La-Roche, Johnson & Johnson, Novartis and Novum Pharmaceuticals over the past 24 months. He has also received additional grant support from AstraZeneca, Bristol-Myers Squibb, Hoffman La-Roche, Merck & Co. and Sepracor Inc. over the past 24 months. In addition, he is a co-inventor on a filed patent application by Yale University (PCTWO06108055A1). Z.Y. and B.S.M. report no competing financial interests.
Studies of glutamate release, glutamate transmission, glutamate receptors and glutamate clearance and metabolism in models of acute and chronic stress. (PDF 447 kb)
- SNARE complex
Soluble NSF (N-ethylmaleimide-sensitive factor) attachment protein (SNAP) receptor complex.
- Learned helplessness
Reduced attempts to avoid aversive stimuli in response to prior exposure to unavoidable stressors. Learned helplessness decreases after antidepressant administration.
FM1-43 is an amphiphilic fluorescent dye that can intercalate into the phospholipid bilayer of biological membranes, allowing the staining of presynaptic vesicles.
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Popoli, M., Yan, Z., McEwen, B. et al. The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission. Nat Rev Neurosci 13, 22–37 (2012). https://doi.org/10.1038/nrn3138
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