From Pathophysiology to Novel Antidepressant Drugs: Glial Contributions to the Pathology and Treatment of Mood Disorders

Sanacora, Gerard; Banasr, Mounira

doi:10.1016/j.biopsych.2013.03.032

Cited by 239Treatment of Major DepressionNeuroscience and Neuropharmacology ResearchTryptophan and brain disorders

From Pathophysiology to Novel Antidepressant Drugs: Glial Contributions to the Pathology and Treatment of Mood Disorders

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Sanacora, Gerard, Banasr, Mounira·2013·Biological Psychiatry

DOI 10.1016/j.biopsych.2013.03.032PMC PMC3688253

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Abstract

Several structural and cellular changes, including marked glial anomalies, have been observed in association with major depressive disorder. Here we review these cellular alterations and highlight the importance of glial cell pathology, especially astroglial dysfunction, in the pathophysiology of neuropsychiatric disorders with a particular interest in major depressive disorder. The functional role of astrocytes in glutamate uptake and glutamate/glutamine cycling is discussed, as is the deleterious effects of chronic stress on glial cell function. Lastly, we discuss the effect of antidepressants on glial cell function and the possibility of targeting glial cells in the quest to develop novel therapeutics.

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Human postmortem studies show lower expression of several astrocyte-function components, mainly in the medial prefrontal cortex and somewhat in the hippocampus, suggesting impaired glutamate-glutamine cycling.
“Several human postmortem studies have also shown reductions in the expression of several components critical to astrocyte function, largely in the mPFC, but also some evidence in the hippocampus, suggesting impaired glutamate-glutamine cycling (133).”
From The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology (2019) · cites this paper as [133]
Emerging evidence indicates impaired glutamate-glutamine cycling in the medial prefrontal cortex and hippocampus in people with major depressive disorder.
“There is also emerging evidence of impaired glutamate-glutamine cycling in the mPFC and hippocampus amongst those with MDD.”
From The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology (2019) · cites this paper as [133]
Subjects with depression display reduced glial density, decreased expression of glutamate reuptake transporters EAAT1 and EAAT2, and decreased enzymatic conversion from glutamate to glutamine.
“Subjects with depression have been shown to display a variety of glutamatergic abnormalities, including reduced glial density, decreased expression of the glutamate reuptake transporters EAAT1 and EAAT2 and decreased enzymatic conversion from glutamate to glutamine [33].”
From Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression (2023) · cites this paper as [33]

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Profiling of behavioral changes and hippocampal gene expression in mice chronically treated with the SSRI paroxetine
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Fluoxetine ameliorates behavioral and neuropathological deficits in a transgenic model mouse of α-synucleinopathy
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Riluzole Augmentation in Treatment-Refractory Obsessive-Compulsive Disorder
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Clomipramine treatment reversed the glial pathology in a chronic unpredictable stress-induced rat model of depression
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Na(+)-dependent, fluoxetine-sensitive serotonin uptake by astrocytes tissue-printed from rat cerebral cortex
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[One hundred books which build up neurology--Rudolf Ludwig Carl Virchow "Die Cellularpathologie in ihrer Begrundung auf physiologische und pathologische Gewebelehre"].
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Riluzole and gabapentinoids activate glutamate transporters to facilitate glutamate-induced glutamate release from cultured astrocytes
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Riluzole produces distinct anxiolytic-like effects in rats without the adverse effects associated with benzodiazepines
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Riluzole rapidly attenuates hyperemotional responses in olfactory bulbectomized rats, an animal model of depression
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Female Early Adult Depression Results in Detrimental Impacts on the Behavioral Performance and Brain Development in Offspring
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Involvement of the mammalian target of rapamycin signaling in the antidepressant-like effect of group II metabotropic glutamate receptor antagonists
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Infusion of gliotoxins or a gap junction blocker in the prelimbic cortex increases alcohol preference in Wistar rats
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Role of astrocytes and altered regulation of spinal glutamatergic neurotransmission in stress-induced visceral hyperalgesia in rats
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Fluoxetine treatment induces EAAT2 expression in rat brain
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Glutamate and disorders of cognition and motivation
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Fluoxetine promotes gliogenesis during neural differentiation in mouse embryonic stem cells
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[3]Virchow RLK 1858 Die Cellularpathologie in ihrer Begründung auf physiologische und pathologische Gewebelehre Berlin A. Hirschwald 21513178

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Differentiation of multipotent neural stem cells derived from Rett syndrome patients is biased toward the astrocytic lineage
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Ketamine and other potential glutamate antidepressants
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Glutamine has antidepressive effects through increments of glutamate and glutamine levels and glutamatergic activity in the medial prefrontal cortex
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Functional magnetic resonance spectroscopy of glutamate in schizophrenia and major depressive disorder: anterior cingulate activity during a color-word Stroop task
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Inflammation-Associated Synaptic Alterations as Shared Threads in Depression and Multiple Sclerosis
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Astrocyte regulation of synaptic signaling in psychiatric disorders
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Early Maternal Deprivation Induces Microglial Activation, Alters Glial Fibrillary Acidic Protein Immunoreactivity and Indoleamine 2,3-Dioxygenase during the Development of Offspring Rats
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Aquaporin‐4 Knockout Exacerbates Corticosterone‐Induced Depression by Inhibiting Astrocyte Function and Hippocampal Neurogenesis
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Evidence supporting a role for astrocytes in the regulation of cognitive flexibility and neuronal oscillations through the Ca2+ binding protein S100β
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Prefrontal cortical GABA abnormalities are associated with reduced hippocampal volume in major depressive disorder
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Regionally selective knockdown of astroglial glutamate transporters in infralimbic cortex induces a depressive phenotype in mice
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Astrocytes are direct cellular targets of lithium treatment: novel roles for lysyl oxidase and peroxisome-proliferator activated receptor-γ as astroglial targets of lithium
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Glial Plasticity in Depression
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Authors: Sanacora, G., & Banasr, M.
Affiliations: Yale University (US)
Corresponding author: Sanacora, Gerard
ORCID: Sanacora, Gerard
Banasr, Mounira
Venue: Biological Psychiatry
Publisher: Elsevier BV
Published: 2013-06
Volume: 73
Issue: 12
Pages: 1172-1179
ISSN: 0006-3223 (ISSN-L)
DOI: 10.1016/j.biopsych.2013.03.032
PMC: PMC3688253
OpenAlex: W2077129553
Cited by: 239
References: 102
Citations by year: 2026: 13 · 2025: 10 · 2024: 14 · 2023: 17 · 2022: 17 · 2021: 22 · 2020: 15 · 2019: 20 · 2018: 21 · 2017: 18 · 2016: 17 · 2015: 27 · 2014: 24 · 2013: 4
FWCI: 3.03
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Biological Psychiatry (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Institute of Mental Health (R01MH085055, R01MH081211, R01 MH08055)
Topics: Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Keywords: glial cells, astrocytes, major depressive disorder, mood disorders, glutamate uptake, chronic stress, antidepressants, neuroinflammation
MeSH terms: Animals, Antidepressive Agents, Cell Communication, Humans, Neuroglia, Neurons, Mood Disorders

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From Pathophysiology to Novel Antidepressant Drugs: Glial Contributions to the Pathology and Treatment of Mood Disorders

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