J Psychiatry Neurosci 2013; 38(4): 276-284
Michelle J. Chandley, PhD; Katalin Szebeni, MD; Attila Szebeni, PhD; Jessica Crawford, BSc; Craig A. Stockmeier, PhD; Gustavo Turecki, MD, PhD; Jose Javier Miguel-Hidalgo, PhD; Gregory A. Ordway, PhD
Chandley, K. Szebeni, A. Szebeni, Crawford, Ordway — Department of Pharmacology, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tenn., USA; Stockmeier, Miguel-Hidalgo — Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, Miss., USA; Turecki — Department of Psychiatry, McGill University, Montréal, Que., Canada
Background: Norepinephrine and glutamate are among several neurotransmitters implicated in the neuropathology of major depressive disorder (MDD). Glia deficits have also been demonstrated in people with MDD, and glia are critical modulators of central glutamatergic transmission. We studied glia in men with MDD in the region of the brain (locus coeruleus; LC) where noradrenergic neuronal cell bodies reside and receive glutamatergic input.
Methods: The expression of 3 glutamate-related genes (SLC1A3, SLC1A2, GLUL) concentrated in glia and a glia gene (GFAP) were measured in postmortem tissues from men with MDD and from paired psychiatrically healthy controls. Initial gene expression analysis of RNA isolated from homogenized tissue (n = 9–10 pairs) containing the LC were followed by detailed analysis of gene expressions in astrocytes and oligodendrocytes (n = 6–7 pairs) laser captured from the LC region. We assessed protein changes in GFAP using immunohistochemistry and immunoblotting (n = 7–14 pairs).
Results: Astrocytes, but not oligodendrocytes, demonstrated robust reductions in the expression of SLC1A3 and SLC1A2, whereas GLUL expression was unchanged. GFAP expression was lower in astrocytes, and we confirmed reduced GFAP protein in the LC using immunostaining methods.
Limitations: Reduced expression of protein products of SLC1A3 and SLC1A2 could not be confirmed because of insufficient amounts of LC tissue for these assays. Whether gene expression abnormalities were associated with only MDD and not with suicide could not be confirmed because most of the decedents who had MDD died by suicide.
Conclusion: Major depressive disorder is associated with unhealthy astrocytes in the noradrenergic LC, characterized here by a reduction in astrocyte glutamate transporter expression. These findings suggest that increased glutamatergic activity in the LC occurs in men with MDD.
Submitted June 8, 2012; Revised Sept. 19, Nov. 15, 2012; Accepted Nov. 28, 2012.
Acknowledgements: The authors gratefully acknowledge the work of Drs. Bryan L. Roth and George Jurjus, and all other psychiatry and brain autopsy personnel involved in the provision of human brain tissues (Cuyahoga County brain collection). The excellent assistance of the Cuyahoga County Coroner’s Office, Cleveland, Ohio, is greatly appreciated. The authors thank the Quebec Suicide Brain Bank, McGill Group for Suicide Studies, at the Douglas Mental Health Institute for provision of brain tissues. The authors also thank the Brain Tissue Donation Program at the University of Pittsburgh for the provision of brain tissues. This research was supported by MH46692, MH80323, MH68499, RR17701, the American Foundation for Suicide Prevention, the Connecticut Mental Health Center and the Department of Mental Health and Addiction Services.
Competing interests: M.J. Chandley, K. Szebeni, A. Szebeni and G.A. Ordway declare having received grant support from the American Foundation for Suicide Prevention, and grant and travel support from the National Institute of Mental Health. J. Crawford declares having received grant support from the American Foundation for Suicide Prevention and the National Institute of Mental Health. C.A. Stockmeier declares having received grant support and scientific instruments from the National Institute of General Medical Sciences. None declared for G. Turecki and J.J. Miguel-Hidalgo.
Contributors: C.A. Stockmeier, G. Turecki and G.A. Ordway designed the study. M.J. Chandley, K. Szebeni, A. Szebeni, J. Crawford and J.J. Miguel-Hidalgo acquired and analyzed the data. C.A. Stockmeier also acquired data; G.A. Ordway also analyzed data. M.J. Chandley and G.A. Ordway wrote the article. K. Szebeni, A. Szebeni, J. Crawford, C.A. Stockmeier, G. Turecki, J.J. Miguel-Hidalgo and G.A. Ordway reviewed the article. All authors approved its publication.
Correspondence to: G.A. Ordway, Department of Biomedical Sciences, James H. Quillen College of Medicine, East Tennessee State University, PO Box 70577, Johnson City TN 37614; Ordway@etsu.edu