Antidepressant-like Effects of Electroconvulsive Seizures Require Adult Neurogenesis in a Neuroendocrine Model of Depression

Abstract

Background Neurogenesis continues throughout life in the hippocampal dentate gyrus. Chronic treatment with monoaminergic antidepressant drugs stimulates hippocampal neurogenesis, and new neurons are required for some antidepressant-like behaviors. Electroconvulsive seizures (ECS), a laboratory model of electroconvulsive therapy (ECT), robustly stimulate hippocampal neurogenesis. Hypothesis ECS requires newborn neurons to improve behavioral deficits in a mouse neuroendocrine model of depression. Methods We utilized immunohistochemistry for doublecortin (DCX), a marker of migrating neuroblasts, to assess the impact of Sham or ECS treatments (1 treatment per day, 7 treatments over 15 days) on hippocampal neurogenesis in animals receiving 6 weeks of either vehicle or chronic corticosterone (CORT) treatment in the drinking water. We conducted tests of anxiety- and depressive-like behavior to investigate the ability of ECS to reverse CORT-induced behavioral deficits. We also determined whether adult neurons are required for the effects of ECS. For these studies we utilized a pharmacogenetic model (hGFAPtk) to conditionally ablate adult born neurons. We then evaluated behavioral indices of depression after Sham or ECS treatments in CORT-treated wild-type animals and CORT-treated animals lacking neurogenesis. Results ECS is able to rescue CORT-induced behavioral deficits in indices of anxiety- and depressive-like behavior. ECS increases both the number and dendritic complexity of adult-born migrating neuroblasts. The ability of ECS to promote antidepressant-like behavior is blocked in mice lacking adult neurogenesis. Conclusion ECS ameliorates a number of anxiety- and depressive-like behaviors caused by chronic exposure to CORT. ECS requires intact hippocampal neurogenesis for its efficacy in these behavioral indices.

Neurotrophic factors and neuroplasticity pathways in the pathophysiology and treatment of depression

“…Similar results have been demonstrated in rodent models of depression (Nakamura et al 2013; Schloesser et al 2015) and non-human primates (Perera et al 2007). …”

The effect of electroconvulsive seizure on survival, neuronal differentiation, and expression of the maturation marker in the adult mouse hippocampus

“…It has been reported that seven ECS repetitions increased the number of DCX (+) cells containing tertiary dendrites (Schloesser et al . ). However, it remains unknown whether ECS enhances dendritic outgrowth in immature neurons.…”

“…While our present data were obtained from mice that did not show a depressive‐like phenotype, a recent report demonstrated that the antidepressant‐like effects of ECS require adult neurogenesis in a neuroendocrine model of depression (Schloesser et al . ). Identifying the molecular mechanisms that underlie each stage of neurogenesis could possibly lead to new targets for the development of antidepressant treatments.…”

“…; Schloesser et al . ). However, the precise contribution of ECS to survival and neuronal differentiation remains unknown.…”

Translating depression biomarkers for improved targeted therapies

“…The molecular mechanisms regulating adult neurogenesis during stress are complex and involve cross talk between inflammatory mediators, neurotrophic factors and cytokines (Egeland et al, 2015). An essential therapeutic role is suggested by experiments showing that antidepressantlike effects of electroconvulsive seizures require adult neurogenesis (Schloesser et al, 2015).…”