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(American Journal of Pathology. 2001;158:453-468.)
© 2001 American Society for Investigative Pathology

Regular Article

Hippocampal Apoptosis in Major Depression Is a Minor Event and Absent from Subareas at Risk for Glucocorticoid Overexposure

Paul J. Lucassen^*, Marianne B. Müller^§, Florian Holsboer^§, Jan Bauer, Anne Holtrop, Jose Wouda, Witte J. G. Hoogendijk^||, E. Ron De Kloet^* and Dick F. Swaab

From the Division of Medical Pharmacology,^*
Leiden Amsterdam Centre For Drug Research, Sylvius Laboratories, Leiden, The Netherlands; the Graduate School Neurosciences Amsterdam,
Netherlands Institute for Brain Research, Amsterdam, The Netherlands; Faculty of Science,
Institute Neurobiology, University of Amsterdam, Amsterdam, The Netherlands; Department of Psychiatry,^||
Faculty of Medicine, Graduate School Neurosciences Amsterdam, Research Institute Neurosciences Free University, Valerius Clinic, Amsterdam, The Netherlands; the Max Planck Institute of Psychiatry,^§
Munich, Germany; and the Division of Neuroimmunology,
Brain Research Institute, University of Vienna, Vienna, Austria

Glucocorticoid (GC) overexposure in animals has been implicated in hippocampal dysfunctioning and neuronal loss. In major depression, hypercortisolemia, hypothalamic-pituitary-adrenocortical-axis alterations, and reduced hippocampal volumes are commonly observed; hence, hippocampal neurodegeneration is also expected. To study possible GC-related pathology, we investigated hippocampal tissue of 15 major-depressed patients, 16 matched controls, and 9 steroid-treated patients, using in situ-end-labeling for DNA fragmentation and apoptosis, and heat-shock protein 70 and nuclear transcription factor B immunocytochemistry for damage-related responses. No obvious massive cell loss was observed in any group. In 11 of 15 depressed patients, rare, but convincing apoptosis was found in entorhinal cortex, subiculum, dentate gyrus, CA1, and CA4. Also in three steroid-treated patients, apoptosis was found. Except for several steroid-treated patients, heat-shock protein 70 staining was generally absent, nor was nuclear transcription factor-B activation found. The detection in 11 of 15 depressed patients, in three steroid-treated, and in one control patient, demonstrates for the first time that apoptosis is involved in steroid-related changes in the human hippocampus. However, in absence of major pyramidal loss, its rare occurrence, that notably was absent from areas at risk for GC damage such as CA3, indicates that apoptosis probably only contributes to a minor extent to the volume changes in depression.

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