Hippocampal apoptosis in major depression is a minor event and absent fromsubareas at risk for glucocorticoid overexposure

Glucocorticoid (GC) overexposure in animals has been implicated in hippocam pal dysfunctioning and neuronal loss. In major depression, hypercortisolemi a, hypothalamic-pituitary-adrenocortical-axis alterations, and reduced hipp ocampal 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 fragmentati on and apoptosis, and heat-shock protein 70 and nuclear transcription facto r kappaB immunohistochemistry for damage-related responses. No obvious mass ive cell loss was observed in any group. In 11 of 15 depressed patients, ra re, but convincing apoptosis was found in entorhinal cortex, subiculum, den tate gyrus, CAI, 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-kap paB activation found. The detection in 11 of 15 depressed patients, in thre e steroid-treated, and in one control patient, demonstrates for the first t ime that apoptosis is involved in steroid-related changes in the human hipp ocampus. However, in absence of major pyramidal loss, its rare occurrence, that notably was absent from areas at risk for GC damage such as CA3, indic ates that apoptosis probably only contributes to a minor extent to the volu me changes in depression.