Reduced levels of NR2A and NR2B subunits of NMDA receptor and PSD-95 in the prefrontal cortex in major depression
Open accessAbstract
Recent neuroimaging and postmortem studies have demonstrated abnormalities in glutamatergic transmission in major depression. Glutamate NMDA (N-methyl-d-aspartate) receptors are one of the major mediators of excitatory neurotransmission in the central nervous system. At synaptic sites, NMDA receptors are linked with postsynaptic density protein-95 (PSD-95) that plays a key role in mediating trafficking, clustering, and downstream signaling events, following receptor activation. In this study, we examined the expression of NMDA receptor subunits NR1, NR2A, and NR2B as well as PSD-95 in the anterior prefrontal cortex (PFC) using Western blot method. Cortical samples were obtained from age, gender and postmortem interval matched depressed and psychiatrically healthy controls. The results revealed that there was a reduced expression of the NMDA receptor subunits NR2A (-54%) and NR2B (-48%), and PSD-95 protein level (-40%) in the PFC of depressed subjects relative to controls, with no change in the NR1 subunit. The alterations in NMDA receptor subunits, especially the NR2A and NR2B, as well as PSD-95 suggest an abnormality in the NMDA receptor signaling in the PFC in major depression. Our findings in conjunction with recent clinical, cellular, and neuroimaging studies further implicate the involvement of glutamate neurotransmission in the pathophysiology of depression. This study provides additional evidence that NMDA receptor complex is a target for discovery of novel antidepressants.
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Levels of synaptic signaling proteins are decreased in major depressive disorder patients in the dorsal lateral prefrontal cortex, the hippocampus, and other forebrain structures.
“Evidence in support of a reduction of synapse number is provided by reports of decreased levels of synaptic signaling proteins in MDD patients, including decreased levels of glutamate receptor subtypes, presynaptic neurotransmitter vesicle-associated proteins, and postsynaptic structural and functional proteins in the dlPFC, the hippocampus, and other forebrain structures (16–19).”
From Synaptic Dysfunction in Depression: Potential Therapeutic Targets (2012) · cites this paper as [18]
The Discussion reports reduced NR2A, NR2B, and PSD-95 in the anterior prefrontal cortex of subjects with MDD. This supports decreased glutamate-receptor and postsynaptic-protein levels in one forebrain region, but not the claimed decreases in the dorsolateral prefrontal cortex or hippocampus, or in presynaptic vesicle-associated proteins. The Discussion also notes unchanged PSD-95 expression reported in the dorsolateral prefrontal cortex and hippocampus. Page numbers were not supplied for these passages. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPatients with depression and related mental illnesses have lower BDNF and/or TRKB mRNA levels, reduced cortical neuron size, lower synaptic protein levels, decreased mTOR signaling, and fewer dendritic spines/synapses in the PFC.
“Postmortem studies have demonstrated that patients with depression and related mental illnesses have lower BDNF and/or TRKB mRNA levels (75–77), reduced cortical neuron size (75, 78, 79), lower synaptic protein levels (80), decreased mTOR signaling (81), and fewer dendritic spines/synapses (82, 83) in the PFC.”
From Psychedelics and Other Psychoplastogens for Treating Mental Illness. (2021) · cites this paper as [80]
Protein expression levels of NMDA subunits NR2A/NR2B and PSD95 are reduced in PFC of MDD patients.
“Protein expression levels of the NMDA subunits NR2A/NR2B and PSD95 are also reduced in PFC of MDD patients 210”
From Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications (2022) · cites this paper as [210]
The expression and function of mTORC1 signaling proteins is reduced in postmortem PFC of depressed subjects, which could contribute to decreased synthesis of synaptic proteins in PFC of depressed subjects.
“It is interesting to note that the expression and function of mTORC1 signaling proteins is reduced in postmortem PFC of depressed subjects, which could contribute to decreased synthesis of synaptic proteins in PFC of depressed subjects50,51.”
From Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants (2016) · cites this paper as [50]
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“Protein expression levels of the NMDA subunits NR2A/NR2B and PSD95 are also reduced in the PFC of MDD patients [210], and RNA-sequencing analyses of postmortem DLPFC from MDD patients similarly revealed the downregulation of genes related to glutamatergic transmission [211].”
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- Authors
- Feyissa, A. M., Chandran, A., Stockmeier, C. A., & Karolewicz, B.
- Affiliations
- University of Mississippi Medical Center (US)
- Corresponding author
- Karolewicz, Beata
- Venue
- Progress in Neuro-Psychopharmacology and Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2009-02
- Volume
- 33
- Issue
- 1
- Pages
- 70-75
- ISSN
- 0278-5846 (ISSN-L)
- PMC
- PMC2655629
- OpenAlex
- W2054535395
- Cited by
- 421
- References
- 46
- Citations by year
- 2026: 19 · 2025: 21 · 2024: 29 · 2023: 28 · 2022: 31 · 2021: 34 · 2020: 34 · 2019: 25 · 2018: 25 · 2017: 14 · 2016: 27 · 2015: 28 · 2014: 24 · 2013: 21 · 2012: 15
- FWCI
- 10.75
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Progress in Neuro-Psychopharmacology and Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5p20rr017701-10)
- National Institute of Mental Health (R01MH067996, MH67996)
- National Center for Research Resources (P20-RR-017701, RR 17701)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- major depressive disorder, NMDA receptor, NR2A, NR2B, NR1 subunit, PSD-95, prefrontal cortex, glutamatergic neurotransmission, postmortem brain, antidepressant targets, glutamatergic dysfunction
- MeSH terms
- Disks Large Homolog 4 Protein, Adult, Carrier Proteins, Major Depressive Disorder, Female, Humans, Male, Membrane Proteins, Middle Aged, Nerve Tissue Proteins, Signal Transduction, Receptors, N-Methyl-D-Aspartate, Prefrontal Cortex, Intracellular Signaling Peptides and Proteins
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