Abstract
Smaller hippocampal volume is reported in major depressive disorder (MDD). We hypothesize that it may be related to fewer granule neurons (GN) in the dentate gyrus (DG), a defect possibly reversible with antidepressants. We studied age-, sex-, and postmortem interval-matched groups: no major psychopathology (controls); unmedicated-MDD; and MDD treated with serotonin reuptake inhibitors (MDD*SSRI) or tricyclics (MDD*TCA). Frozen right hippocampi were fixed, sectioned (50 μm), immunostained with neuronal nuclear marker (NeuN), and counterstained with hematoxylin. GN and glial number, and DG and granule cell layer (GCL) volumes were stereologically estimated. Fewer GNs in the anterior DG were present in unmedicated-MDDs compared with controls (p=0.013). Younger age of MDD onset correlated with fewer GNs (p=0.021). Unmedicated-MDDs had fewer mid-DG GNs than MDD*SSRIs (p=0.028) and controls (p=0.032). Anterior GCL glial number did not differ between groups. Anterior/mid GCL volume was smaller in unmedicated-MDDs vs controls (p=0.008) and larger in MDD*SSRIs vs unmedicated-MDDs (p<0.001), MDD*TCAs (p<0.001), and controls (p<0.001). Anterior GCL volume and GN number (r=0.594, p=0.001), and mid DG volume and GN number (r=0.398, p=0.044) were correlated. Anterior DG capillary density correlated with GN number (p=0.027), and with GCL (p=0.024) and DG (r=0.400, p=0.047) volumes. Posterior DG volume and GN number did not differ between groups. Fewer GNs in unmedicated-MDD without fewer neuronal progenitor cells, as previously reported, suggests a cell maturation or survival defect, perhaps related to MDD duration. This may contribute to a smaller hippocampus and is potentially reversed by SSRIs. Postmortem studies are correlative and animal studies are needed to test implied causal relationships.
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Acknowledgements
We thank Mihran J Bakalian, BA, for data management and graphics preparation, Tanya H Butt, BS, for immunohistochemistry and stereology work. This study was supported by MH83862, MH94888, MH64168, the American Foundation for Suicide Prevention and the Diane Goldberg Foundation.
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Maura Boldrini, Adrienne Santiago, Andrew Dwork, Gorazd Rosoklija, Hadassah Tamir, and Victoria Arango declare that, except for income received from their primary employer, no financial support or compensation has been received from any individual or corporate entity over the past three years for research or professional services and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest. Dr Dwork received loans and gifts of equipment and software from Olympus and Visiopharm for research unrelated to this study. Dr René Hen receives compensation as a consultant for Roche and Lundbeck. Dr J John Mann received past unrelated grants from GlaxoSmithKline and Novartis.
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Boldrini, M., Santiago, A., Hen, R. et al. Hippocampal Granule Neuron Number and Dentate Gyrus Volume in Antidepressant-Treated and Untreated Major Depression. Neuropsychopharmacol 38, 1068–1077 (2013). https://doi.org/10.1038/npp.2013.5
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DOI: https://doi.org/10.1038/npp.2013.5
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