Repeated Stress Causes Cognitive Impairment by Suppressing Glutamate Receptor Expression and Function in Prefrontal Cortex
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Chronic stress could trigger maladaptive changes associated with stress-related mental disorders; however, the underlying mechanisms remain elusive. In this study, we found that exposing juvenile male rats to repeated stress significantly impaired the temporal order recognition memory, a cognitive process controlled by the prefrontal cortex (PFC). Concomitantly, significantly reduced AMPAR- and NMDAR-mediated synaptic transmission and glutamate receptor expression were found in PFC pyramidal neurons from repeatedly stressed animals. All these effects relied on activation of glucocorticoid receptors and the subsequent enhancement of ubiquitin/proteasome-mediated degradation of GluR1 and NR1 subunits, which was controlled by the E3 ubiquitin ligase Nedd4-1 and Fbx2, respectively. Inhibition of proteasomes or knockdown of Nedd4-1 and Fbx2 in PFC prevented the loss of glutamatergic responses and recognition memory in stressed animals. Our results suggest that repeated stress dampens PFC glutamatergic transmission by facilitating glutamate receptor turnover, which causes the detrimental effect on PFC-dependent cognitive processes.
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In animals, chronic stress results in prolonged release of glucocorticoids and leads to hypertrophy of the amygdala and nucleus accumbens, atrophy of the hippocampus and prefrontal cortex, and functional impairment of the PFC.
“In animals, chronic stress results in the prolonged release of glucocorticoids and leads to hypertrophy of the amygdala and nucleus accumbens, atrophy of the hippocampus and prefrontal cortex (PFC), and functional impairment of the PFC (44–55).”
From Psychedelics and Other Psychoplastogens for Treating Mental Illness. (2021) · cites this paper as [49]
The Introduction and Discussion (page numbers unavailable) describe stress-related PFC atrophy and impairment, hippocampal dendritic atrophy, and amygdala dendritic growth. Our copy does not establish hypertrophy of the nucleus accumbens or prolonged glucocorticoid release; the hippocampal and PFC findings concern neuronal structures rather than atrophy of the regions as a whole. (LLM, conf=0.87)
Experimental — accuracy not yet measuredA prominent loss of GluR1 and NR1 subunit expression in PFC pyramidal neurons from repeatedly stressed animals leads to depression of AMPAR- and NMDAR-mediated synaptic currents.
“A prominent loss of GluR1 and NR1 subunit expression has been found in PFC pyramidal neurons from repeatedly stressed animals, which leads to the depression of AMPAR- and NMDAR-mediated synaptic currents 110.”
From Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications (2022) · cites this paper as [110]
This stress-induced loss of glutamate receptor expression is attributable to increased ubiquitin/proteasome-mediated degradation of GluR1 and NR1 controlled by E3 ubiquitin ligases Nedd4 and Fbx2.
“This stress-induced loss of glutamate receptor expression is attributable to the increased ubiquitin/proteasome-mediated degradation of GluR1 and NR1 that is controlled by E3 ubiquitin ligases Nedd4 and Fbx2”
From Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications (2022) · cites this paper as [110]
In the medial prefrontal cortex, some studies report lower chronic stress-related glutamate receptor expression, which has been speculated to protect against excessive glutamate signaling and excitotoxicity.
“A different pattern has been described in the mPFC, with some reporting reduced chronic stress-related glutamate receptor expression, which has been speculated as a potential protective mechanism against excessive glutamate signaling and excitoxicity (e.g., 124–125).”
From The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology (2019) · cites this paper as [125]
In vivo proton magnetic resonance spectroscopy detected elevated glutamate levels in ventromedial prefrontal cortex/anterior cingulate cortex in untreated major depressive disorder, consistent with a meta-analysis finding higher glutamate/glutamine concentrations in medial frontal cortex of unmedicated major depressive disorder but not antidepressant-treated patients.
“In vivo proton magnetic resonance spectroscopy (1H MRS) detected elevated glutamate levels in ventromedial prefrontal cortex/anterior cingulate cortex in untreated MDD161 consistent with a recent meta-analysis of MRS imaging studies that found higher glutamate/glutamine concentrations in medial frontal cortex of unmedicated MDD but not in antidepressant-treated patients162.”
From Dysregulation of adult hippocampal neuroplasticity in major depression: Pathogenesis and therapeutic implications (2022) · cites this paper as [162]
Chronic stress decreases synaptic excitation of prefrontal pyramidal cells.
“Indeed, consistent with spine loss, chronic stress decreases the synaptic excitation of pyramidal cells in the PFC [191].”
From Plasticity of synapses and reward circuit function in the genesis and treatment of depression (2023) · cites this paper as [191]
The deleterious effects of repeated corticosterone exposure correlate with decreased glutamate receptor expression and AMPA-R activity.
“the deleterious effects of repeated corticosterone exposure correlate with decreased glutamate receptor expression and AMPA-R activity (Yuen et al 2012).”
From Prefrontal cortex executive processes affected by stress in health and disease (2018) · cites this paper as Yuen et al 2012
Repeated corticosterone administration impairs temporal order recognition in rats.
“repeated corticosterone administration impairs temporal order recognition in rats (Yuen et al 2012)”
From Prefrontal cortex executive processes affected by stress in health and disease (2018) · cites this paper as Yuen et al 2012
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“Behind these changes, a variety of molecular processes related to glutamate cycling and release may be implicated, including the decreased expression NMDA-Rs (39–41), AMPARs (41, 42), or mGluRs (43), which have been reported both in humans and animal models of depression, as well as in postmortem brains of suicide vic…”
BackgroundPsilocybin induces rapid and persistent growth of dendritic spines in frontal cortex <i>in vivo</i>
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“Likewise, synaptic deficiencies, including loss of dendritic arborization, reduced spine density, and damped neurotransmission, are present in the frontal cortex of rodent chronic stress models (Cook and Wellman, 2004; Liston et al., 2006; Radley et al., 2004; Yuen et al., 2012).”
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A precision medicine approach to pharmacological adjuncts to extinction: A call to broaden research
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- Authors
- Yuen, E. Y., Wei, J., Liu, W., Zhong, P., Li, X., & Yan, Z.
- Affiliations
- University at Buffalo, State University of New York (US)
- Corresponding author
- Yan, Zhen
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2012-03
- Volume
- 73
- Issue
- 5
- Pages
- 962-977
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC3302010
- OpenAlex
- W2070005343
- Cited by
- 558
- References
- 67
- Citations by year
- 2026: 18 · 2025: 40 · 2024: 32 · 2023: 37 · 2022: 43 · 2021: 50 · 2020: 37 · 2019: 53 · 2018: 43 · 2017: 51 · 2016: 43 · 2015: 46 · 2014: 32 · 2013: 26 · 2012: 7
- FWCI
- 14.63
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 539 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (MH84233, MH85774)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- repeated stress, chronic stress, cognitive impairment, prefrontal cortex, glutamate receptors, AMPA receptors, NMDA receptor, glucocorticoid receptor, ubiquitin-proteasome degradation, GluR1, NR1 subunit, NEDD4-1, synaptic transmission, glutamatergic neurotransmission, stress-related disorders
- MeSH terms
- Nedd4 Ubiquitin Protein Ligases, Analysis of Variance, Animals, Bicuculline, Cognition Disorders, Disease Models, Animal, Male, Neuropsychological Tests, Restraint, Physical, Stress, Psychological, 2-Amino-5-phosphonovalerate, Rats, Sprague-Dawley, Prefrontal Cortex, Receptors, Glutamate, Pyramidal Cells, Excitatory Amino Acid Antagonists, 6-Cyano-7-nitroquinoxaline-2,3-dione, Excitatory Postsynaptic Potentials, Recognition, Psychology, RNA, Small Interfering, Ubiquitin-Protein Ligases, F-Box Proteins, Immunoprecipitation, Rats, Endosomal Sorting Complexes Required for Transport, GABA-A Receptor Antagonists, In Vitro Techniques
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