Hippocampal neurogenesis and antidepressive therapy: shocking relations

Abstract

Speculations on the involvement of hippocampal neurogenesis, a form of neuronal plasticity, in the aetiology of depression and the mode of action of antidepressive therapies, started to arise more than a decade ago. But still, conclusive evidence that adult neurogenesis contributes to antidepressive effects of pharmacological and physical therapies has not been generated yet. This review revisits recent findings on the close relation between the mode(s) of action of electroconvulsive therapy (ECT), a powerful intervention used as second-line treatment of major depression disorders, and the neurogenic response to ECT. Following application of electroconvulsive shocks, intricate interactions between neurogenesis, angiogenesis, and microglia activation, the hypothalamic-pituitary-adrenal axis and the secretion of neurotrophic factors have been documented. Furthermore, considering the fact that neurogenesis strongly diminishes along aging, we investigated the response to electroconvulsive shocks in young as well as in aged cohorts of mice.

Figure 1

Differentiation and maturation of adult neural stem cells. The process from stem cell division to the fully integrated mature neuron in the dentate gyrus takes approximately 30 days in rodents. Specific markers characterize the various maturation stages (e.g., DCX for neuroblasts). Experimental ECS or pharmacological treatments can influence neurogenesis at various stages; experimental ECS is also reported to activate quiescent stem cells.

Figure 2

Representative micrographs showing the detection of BrdU-labelled cells in the dentate gyrus of a 2-month-old mouse from (a) the sham group or (b) the experimental ECS group. Scale bar: 200 μm. (c) The number of BrdU⁺ cells was determined to estimate the rates of cell proliferation in the dorsal DG of 2- and 20-month-old mice. Both groups showed a highly significant enhancement in cell proliferation following experimental ECS-treatment. Two months, P < 0.0001 (***); 20 months, P = 0.0004 (***).

Figure 3

Detection of GFAP in the dentate gyrus of (a) sham-treated or (b) ECS-treated mouse of the 2 months of age cohort, scale bar in (a) 100 μm. (c) Graph showing percentage of area covered by GFAP-expressing cells in the granular layer of dentate gyrus in 2- and 20-month-old mice following ECS or sham treatment. A two-way ANOVA detected a significant increase of the GFAP expression upon experimental ECS (P = 0.0043 (**)). Bonferroni post hoc test revealed that the significance resulted from differences in the 2-month-old group (P < 0.05).

Figure 4

(a) Detection of microglia in the granular layer (GL) of a 2-month-old mouse based on the expression of Iba1 (white) (ML: molecular layer). Scale bar: 50 μm. (b) Microglia volume was estimated according to the percentage of the surface covered by Iba1⁺ labelling in the granular layer of 2- and 20-month-old mice following ECS or sham treatment. Two-way ANOVA revealed upon ECS a significant increase of Iba1-labeled surface in the dentate gyrus of both age groups (P = 0.0475).

Figure 5

(a) Detection of blood vessels in the granular layer of the dorsal dentate gyrus with B. simplicifolia lectin (red) (inset, overview of the dentate gyrus with position of the field of view, ML: molecular layer, GL: granular layer). Scale bar: 50 μm. (b) No significant differences in blood vessel density could be detected following ECS. Interestingly, aged brains had a slightly decreased vessel density compared to the younger group (P = 0.0122).

Figure 6

(a) Overview of a murine hippocampus with its substructures cornu ammonis (CA) 1–3, lateral ventricle (LV), stratum lacunosum moleculare (SLM), molecular layer (ML), granular layer (GL), and the hilus. Scale bar: 200 μm. (b) Volume of the dorsal dentate gyrus of 2- and 20-month-old mice following ECS or sham-treatment. Young mice showed a significant increase of volume after ECS (2 months, P = 0.002 (**); 20 months (ns)).