Mental Disorders; Chemicals and Drugs
Over the last ten years we have witnessed a fundamental change in our understanding of the neurobiology of mood disorders, including major depression disorder (MDD). In addition to chemical imbalances, it is now clear that there are significant structural alterations of limbic brain regions associated with depression, and postmortem studies of MDD patients demonstrate morphological changes including decreases in neuronal size and glial loss that could underlie these changes. We believe that a better understanding of the cellular mechanisms involved in these morphological alteration could offers hope for the development of new and more efficient treatments for depression.
Extensive Research Description
addition to chemical imbalances, it is now clear that there are significant
structural alterations of limbic brain regions associated with depression, and
postmortem studies of MDD patients demonstrate morphological changes including
decreases in neuronal size and glial loss that could underlie these changes.
are the consistent reports of decreased number and function of glia in limbic
regions, particularly the prefrontal cortex, suggesting a role for glia in the
neurobiology of MDD. These
studies have focused primarily on astrocytes, although changes in
oligodendrocytes have also been reported. The critical role of astrocytes in
providing metabolic and trophic support raise the possibility that the glial
loss could contribute to decreased size and function of neurons.
However, it is not clear if glial reductions are causally related to MDD, playing a direct role in the expression of depressive symptoms, or are a consequence of the illness. A related question is whether preventing glial deficits would alleviate the symptoms of depression. Although these issues are difficult to address in MDD patients, progress is being made in basic research studies. Exposing rats to chronic stress results in glial reductions, as well as neuronal atrophy similar to the changes observed in MDD patients. Chronic stress also reduces the expression of specific astrocyte markers, as well as astrocytic metabolism in the prefrontal cortex. In rodents, chronic stress also results in behavioral alterations in tests measuring anhedonia and helplessness, core symptoms of depression. Employing these tests, the influence of compounds that disrupt astrocytic function or that cause astrocytic death, on depressive-like behaviors has been determined. Infusions of a toxin that causes glial death into the prefrontal cortex induced anhedonia and helplessness and increases the susceptibility to stress. These findings provide the first evidence that loss of glia may contribute to depressive symptoms and is not merely a side effect. Studies using pharmacologic and genetic approaches aiming to identify the subtype(s) of glial cells mediating these effects and the molecular determinants involved in glial loss are currently underway.
Recently, there has been considerable enthusiasm for studying the antidepressant actions of agents that enhance glial glutamate uptake, a key function of astrocytes. One such drug is riluzole, known to delay the progression of amyotrophic lateral sclerosis, a neurodegenerative disease with documented astrocytic dysfunction. Riluzole is reported to have antidepressant actions in MDD patients and in rodents, and prevents the decrease in glial metabolism and loss induced by chronic stress. Although additional studies with agents that selectively increase or protect glial function are required to further test this hypothesis, this preliminary research offers hope for an entirely new area, targeting glial function for the treatment of depression.
- Action of stress and antidepressants on adult neurogenesis in the hippocampus
- Action of stress and antidepressants on gliogenesis in the prefrontal cortex
- Action of stress and antidepressants on mature glial cells
- Implication of glial cells in the depression and stress related behaviors
- Glial function as a new target for antidepressant action
- Su XW, Li XY, Banasr M, Koo JK, Shahid M, Henry B, and Duman RS (2009) Chronic treatment with an AMPA receptor potentiator increases neuronal cell proliferation and survival in adult rodent hippocampus. Psychopharmacology.
- Greene J, Banasr M, Lee B, Warner-Schmidt J, and Duman (2009) Vascular Endothelial Growth Factor Signaling is Required for the Behavioral Actions of Antidepressant Treatment: Pharmacological and Cellular Characterization. Neuropsychopharmacology.
- Banasr M, Choudhury GM, Newton SS, Twillinger R, Duman RS, Behar KL, Sanacora G (2008) Glial pathology in an animal model of depression: Reversal of stress-induced cellular, metabolic and behavioral deficits by the glutamate modulating drug riluzole. Mol
- Banasr M, Duman RS (2008) Glial Loss in the Prefrontal Cortex Is Sufficient to Induce Depressive-like Behaviors. Biol Psychiatry Nov 15;64(10):863-70.
- Choudhury GM, Banasr M, de Graaf RA., Rothman DL, Behar KL, Sanacora G (2008) Chronic Riluzole Treatment Increases Glucose Metabolism in Rat Prefrontal Cortex and Hippocampus. J Cereb Blood Flow Metab Jul 16 Dec;28(12):1892-7.
- Banasr M, Valentine GW, Li XY, Gourley SL, Taylor JR, Duman RS (2007) Chronic unpredictable stress decreases cell proliferation in the cerebral cortex of the adult rat. Biol Psychiatry 62:496-504.
- Banasr M, Duman RS (2007) Regulation of neurogenesis and gliogenesis by stress and antidepressant treatment. CNS Neurol Disord Drug Targets 6:311-320.