Original articleLow glial numbers in the amygdala in major depressive disorder
Introduction
Several recent studies have indicated that the orbital and medial parts of the prefrontal cortex (PFC) are functionally and structurally altered in mood disorders. Functional imaging studies have shown changes in blood flow and glucose metabolism related to both major depressive disorder (MDD) and bipolar disorder (BD) in several of these areas Drevets et al 1992, Drevets 1998, Drevets 2000, Mayberg et al 1997, Critchley et al 2000. Decreases in cortical volume and resting cerebral glucose metabolism have been reported in the subgenual cortex, especially in the left hemisphere Drevets et al 1997, Öngür et al 1998a. This change was found to be associated with significant reductions in glial cell numbers in familial MDD and familial BD, while neuron numbers remained unchanged (Öngür et al 1998a). Similar findings of reductions in glial density have also been reported in the orbital cortex, the anterior cingulate cortex, and the dorsolateral prefrontal cortex, based on a laminar analysis of these regions Rajkowska et al 1999, Price et al 2001, Cotter et al 2001a. On the other hand, no glial cell reduction was found in area 3b of the somatosensory cortex of depressed cases, suggesting that glial cell reduction in mood disorders is restricted to specific brain structures (Öngür et al 1998a).
The amygdala is strongly interconnected with the orbital and medial PFC (Carmichael and Price 1995), and has been implicated in emotional behavior and mood disorders. Both the amygdala and the PFC have connections to several hypothalamic and brainstem structures involved in the visceral reactions to emotional stimuli An et al 1998, Öngür et al 1998b, Rempel-Clower and Barbas 1998, Öngür and Price 2000. Damage to the amygdala produces diminished fear, hypoemotionality, decreased aggression, increased passivity, and deficits in memory related to emotion Klüver and Bucy 1939, Aggleton and Passingham 1981, Cahill et al 1995, Emery et al 2001. Functional imaging studies have shown that the amygdala is activated in subjects viewing sad faces (Blair et al 1999), as well as fearful faces Breiter et al 1996, Morris et al 1996, Morris et al 1998, Whalen et al 1998. Most significantly, activity in the amygdala is increased in mood disorders. Drevets et al (1992, 2000) reported a significant increase in resting cerebral blood flow and glucose metabolism in the left amygdala of depressed patients with familial pure depressive disease. Ketter et al (2001) found abnormally elevated metabolism in the right amygdala in depressed BD patients, and Abercrombie et al (1998) reported that metabolism in the right amygdala of patients with MDD correlated with depression severity.
There have also been reports of volume changes in the amygdala in mood disorder subjects. An MRI study reported a 17% reduction in the volume of the core amygdala nuclei (the basal nucleus, accessory basal nucleus, and lateral nucleus) was in recurrent MDD patients, without a significant change in total amygdala volume (Sheline et al 1998). Studies of BD have been divergent. One study reported a decrease in the volume of the left amygdala in BD relative to control subjects (Pearlson et al 1997), while two others reported increased amygdala volume Altshuler et al 1998, Altshuler et al 2000, Strakowski et al 1999, and a third reported no change (Swayze et al 1992).
This study used stereological methods to determine the number of neurons and glia in the amygdala and the adjacent, closely related entorhinal cortex in the brains of subjects with MDD and BD, compared with age-matched controls. Because of recent reports that treatment with the mood stabilizers Li and valproate (VPA) can increase levels of cell protective agent BCL-2 (Manji et al 2000), we also examined the relation between these drugs and neuronal or glial numbers.
Section snippets
Subject specimens
Tissue blocks through the amygdala from either the right or left hemisphere of 39 cases (8 MDD, 19 BD, and 12 normal controls) were obtained from the Harvard Brain Tissue Resource Center. Original case numbers were recorded and the blocks were then coded to ensure that the histopathological analysis was blind to subject diagnosis. The diagnosis of MDD or BD was assigned based upon chart review and family interview by the HBTRC psychiatrist using DSM-IV criteria. All of the MDD and BD cases had
Clinical characteristics of the subjects
Suicide was listed as the cause of death for four of the BD cases and two MDD cases (Table 1). At the time of death, all but two of the BD cases had been chronically treated with one or both of the mood stabilizing drugs Li and VPA (divalpoex sodium, Depakote). One MDD case had been treated with Li to augment the response to antidepressant drugs. In regards to other medications, three MDD and five BD cases were receiving antidepressant drugs, zero MDD and five BD subjects were on antipsychotic
Discussion
This study extends to the amygdala the previous findings of glial cell reduction in mood disorders in the frontal cortex Öngür et al 1998a, Rajkowska et al 1999, Cotter et al 2001a, Cotter et al 2001b. The corresponding reductions in glial measures in the entorhinal cortex were much smaller than those in the amygdala. This result, together with the previous finding that glial reduction was not seen in somatosensory cortical area 3b (Öngür et al 1998a), suggests that glial changes in mood
The role of glia in the brain
The Nissl method does not allow ready differentiation between astrocytes, oligodendrocytes, and microglia. Because of this it is not yet known whether one type of glia is accounting for the significant reductions seen, or whether there are more uniform drops in more than one type of glial cell. To date, attempts in this lab to resolve this question by counting cells stained with glial fibrillary acidic protein (GFAP) have been inconclusive. In addition, it is still not clear whether glial
Mood stabilizers and glial reduction
An intriguing aspect of the present data are the suggestion that the mood stabilizers Li and VPA may attenuate or reverse the decrease in glial numbers in mood disorders. This result is based on very few cases, and must be considered tentative until confirmed in more cases and/or in other regions of the brain. A similar increase in glia has been reported in the dorsolateral frontal cortex of monkeys treated with antipsychotic drugs (Selemon et al 1999), but previous studies have not reported an
Acknowledgements
This project was supported by NIH research grants DC 00093 (to JLP) and MH 01713 (to WCD). We would like to thank Dr. Francine Benes, Dr. Stephen Vincent, and others at the Harvard Brain Tissue Resource Center for providing the brain tissue used in the study. We would also like to thank Mr. Hieu Van Luu for his excellent technical assistance.
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