Reduced density of glutamine synthetase immunoreactive astrocytes in different cortical areas in major depression but not in bipolar I disorder

Abstract

There is increasing evidence for disturbances within the glutamate system in patients with affective disorders, which involve disruptions of the glutamate-glutamine-cycle. The mainly astroglia-located enzyme glutamine synthetase (GS) catalyzes the ATP-dependent condensation of ammonia and glutamate to form glutamine, thus playing a central role in glutamate and glutamine homoeostasis. However, GS is also expressed in numerous oligodendrocytes (OLs), another class of glial cells implicated in mood disorder pathology. To learn more about the role of glia-associated GS in mental illnesses, we decided to find out if numerical densities of glial cells immunostained for the enzyme protein differ between subjects with major depressive disorder, bipolar disorder (BD), and psychically healthy control cases. Counting of GS expressing astrocytes (ACs) and OLs in eight cortical and two subcortical brain regions of subjects with mood disorder (N = 14), BD (N = 15), and controls (N = 16) revealed that in major depression the densities of ACs were significantly reduced in some cortical but not subcortical gray matter areas, whereas no changes were found for OLs. In BD no alterations of GS-immunoreactive glia were found. From our findings we conclude that (1) GS expressing ACs are prominently involved in glutamate-related disturbances in major depression, but not in BD and (2) GS expressing OLs, though being present in significant numbers in prefrontal cortical areas, play a minor (if any) role in mood disorder pathology. The latter assumption is supported by findings of others showing that - at least in the mouse brain cortex - GS immunoreactive oligodendroglial cells are unable to contribute to the glutamate-glutamine-cycle due to the complete lack of amino acid transporters (Takasaki et al., 2010).

Keywords: astroglia; bipolar disorder; cortex; glutamine synthetase; immunocytochemistry; major depression; oligodendroglia.

FIGURE 1

Immunolocalization of GS in cortical and subcortical human brain glial cells in MDD, BD, and controls. (A) GS-immunoreactive ACs and OLs (asterisk) in the pACC (control case). Bar = 20 μm. (B) GS-immunoreactive ACs and OLs (asterisks) in the pACC (MDD subject). Bar = 20 μm. (C) GS-immunoreactive ACs and OLs (asterisk) in the pACC (BD subject). Bar = 20 μm. (D) GS-immunoreactive ACs and OLs (asterisks) in the sACC (control case). Bar = 20 μm.(E) GS-expressing ACs and OLs (asterisk) in the sACC (MDD subject). Bar = 20 μm.(F) GS-expressing ACs and OLs (asterisk) in the DLPFC (BD subject). Bar = 20 μm. (G) GS-immunopositive ACs in the AiC (control case). Bar = 20 μm. (H) GS-expressing ACs in the NAc (control case). Bar = 24 μm. (I) GS-immunoreactive OLs (asterisks) in the pACC (control case). Bar = 20 μm. (J) Specificity control reaction. After preabsorption of the primary antiserum with recombinant GS protein no specific immunostaining is visible. Bar = 30 μm.

FIGURE 2

Numerical densities of GS-expressing glial cells (ACs and OLs) in the DLPFC of subjects with MDD, BD, and controls. Compared with controls the density of GS-expressing ACs is significantly reduced in MDD cases (AC left I–III, p = 0.029; AC right I–III, p = 0.046).

FIGURE 3

Numerical densities of GS-expressing glial cells (ACs and OLs) in the pACC of subjects with MDD, BD, and controls. No significant alterations were found in this brain region.

FIGURE 4

Numerical densities of GS-expressing glial cells (ACs and OLs) in the sACC of subjects with MDD, BD, and controls. Compared with controls the density of GS-expressing ACs is significantly reduced in MDD cases (AC left I–III, p = 0.021).

FIGURE 5

Numerical densities of GS-expressing glial cells (ACs and OLs) in the AiC of subjects with MDD, BD, and controls. Compared with controls the density of GS-expressing ACs is significantly reduced in MDD cases (AiC left I–III, p = 0.002; AiC right I–III, p = 0.001; AiC right IV–VI, p = 0.015).

FIGURE 6

Numerical densities of GS-expressing glial cells (ACs and OLs) in the NAc of subjects with MDD, BD, and controls. No significant alterations were found in this brain region.

FIGURE 7

Numerical densities of GS-expressing glial cells in the AiC of suicide completers with MDD, non-suicide completers with MDD, suicide completers with BD, non-suicide completers with BD, and controls. No significant alterations were found.