Increased hippocampal neurogenesis and p21 expression in depression: dependent on antidepressants, sex, age, and antipsychotic exposure

Abstract

The mammalian hippocampus continues to generate new neurons throughout life. The function of adult-generated neurons remains controversial, but adult neurogenesis in the hippocampus is related to depression. Studies show that neurogenesis in the hippocampus is regulated by antidepressants in both humans and rodents, but no studies have examined the effects of age, sex, or antipsychotic exposure on the relationship between depression, antidepressant exposure, and hippocampal neurogenesis in humans. Hippocampal sections were obtained from the Stanley Medical Research Institute and were immunohistochemically labeled for the immature neuron marker doublecortin and the cell cycle arrest marker p21. We compared the number of cells in the granule cell layer and subgranular zone that expressed these proteins in brains from control subjects (n=12), patients with major depressive disorder (MDD) without psychotic symptoms (n=12), and patients with MDD and psychotic symptoms (n=12). We show here that the density of doublecortin/NeuN expression was increased in MDD patients compared with controls and MDD patients with psychosis, with the effect greater in women. Further, we show that older depressed patients without psychosis had higher levels of p21/NeuN expression and that depressed individuals prescribed antidepressants had higher levels of p21/NeuN expression, but only in older women. We show for the first time that changes in neurogenesis due to prescribed antidepressants or depression are dependent on age, sex, and the presence of antipsychotics or psychotic symptoms.

Figure 1

Photomicrographs of representative labeling of (a) low magnification stitched image of the granule cell layer (GCL) and (b) high magnification images of NeuN (red) counterstained with DAPI (blue). Panels (c) ( × 400) and (d) ( × 1000) show representative doublecortin labeling in the GCL and subgranular zone. Panels (e) ( × 400) and (f) ( × 1000) show the location of strongly labeled p21 cells at the border of the GCL and the subgranular zone.

Figure 2

(a) p21 expression correlates with patient age. There was a significant positive correlation between p21 expression and age in depressed women (r=0.70, p=0.016) but not men (r=0.42, p=0.15). Age and p21 expression were not significantly correlated with each other in control or depressed patients with psychotic symptoms but were significantly positively correlated in depressed patients without psychotic symptoms (r=0.61, p=0.037). (b) NeuN density correlates with age of onset of depression. There was a significant positive correlation between NeuN density in the GCL of the hippocampus and age of onset of depression. However, this correlation was only significant in depressed patients with psychosis (r=0.61, p=0.035).

Figure 3

Increased density of p21/NeuN expression in older depressed patients. (a) There was a significantly greater density of p21/NeuN-expressing cells in the dentate gyrus of older depressed patients (>50 years) compared with controls. (b) Older women (>50 years) had significantly greater density of p21/NeuN-expressing cells than younger men and women. (c) Older women that had been prescribed antidepressants had significantly greater density of p21/NeuN-expressing cells than all other groups. Data shown is mean+SEM. (d) Photomicrographs show representative density of p21 expression in patients that were diagnosed as depressed (<50 or >50 years), depressed with psychosis, or controls. *P⩽0.05.

Figure 4

The density of doublecortin (DCX)/NeuN expression in the dentate gyrus is increased in depressed patients. (a) The density of DCX/NeuN expression was increased in depressed patients compared with depressed patients with psychosis (p=0.02) and with a strong trend in controls (p=0.08). (b) The density of DCX/NeuN expression was significantly greater in depressed women compared with all other groups. (c) Depressed patients prescribed antidepressants had greater density of DCX/NeuN expression compared with depressed patients with psychosis prescribed antidepressants (compare white bars, p=0.008). (d) In younger (age <50 years), but not older (age >50 years) age groups, depressed patients that were not prescribed antipsychotics had significantly greater DCX/NeuN expression compared with all other groups. Data shown is mean+SEM. (e) Representative DCX expression is shown from depressed patients, depressed patients with psychosis, and controls. *P⩽0.05.