Gene Profile of Electroconvulsive Seizures: Induction of Neurotrophic and Angiogenic Factors

Abstract

Electroconvulsive seizure therapy (ECS) is a clinically proven treatment for depression and is often effective even in patients resistant to chemical antidepressants. However, the molecular mechanisms underlying the therapeutic efficacy of ECS are not fully understood. One theory that has gained attention is that ECS and other antidepressants increase the expression of select neurotrophic factors that could reverse or block the atrophy and cell loss resulting from stress and depression. To further address this topic, we examined the expression of other neurotrophic-growth factors and related signaling pathways in the hippocampus in response to ECS using a custom growth factor microarray chip. We report the regulation of several genes that are involved in growth factor and angiogenic-endothelial signaling, including neuritin, stem cell factor, vascular endothelial growth factor (VEGF), VGF (nonacronymic), cyclooxygenase-2, and tissue inhibitor of matrix metalloproteinase-1. Some of these, as well as other growth factors identified, including VEGF, basic fibroblast growth factor, and brain-derived neurotrophic factor, have roles in mediating neurogenesis and cell proliferation in the adult brain. We also examined gene expression in the choroid plexus and found several growth factors that are enriched in this vascular tissue as well as regulated by ECS. These data suggest that an amplification of growth factor signaling combined with angiogenic mechanisms could have an important role in the molecular action of ECS. This study demonstrates the applicability of custom-focused microarray technology in addressing hypothesis-driven questions regarding the action of antidepressants.

Stress coping stimulates hippocampal neurogenesis in adult monkeys

“…In songbirds and rodents, adult neurogenesis is mediated, in part, by the expression of genes involved in proliferation, survival, and integration of neurons into functional circuits (38)(39)(40). Several genes identified in earlier studies are supported to various degrees by our microarray results for squirrel monkeys.…”

“…Brain-derived neurotrophic factor (BDNF) gene expression correlated with learning but not neurogenesis, whereas growth factor receptorbound protein 2 (GRB2) gene expression correlated with neurogenesis but not learning performance. Previously, these genes have been associated with learning and hippocampal neurogenesis in rodents (39)(40)(41). Of the five genes in monkeys that correlated both with learning and hippocampal neurogenesis, the most wellknown encodes IGF1, which acts locally to increase neurogenesis through PI3K/Akt signaling (42).…”

Genetic Regulation of Behavioral and Neuronal Responses to Fluoxetine

“…We identified 83 unique genes upregulated and 17 genes downregulated in the brains of fluoxetine-treated mice. A number of these genes, including Bdnf, Npy, Egr3, and Cox2, have also been shown to be induced by electroconvulsive seizures, another type of antidepressant treatment (Newton et al, 2003). It is likely that the upregulated genes are associated specifically with the behavioral and/or neuronal response to treatment, as none of 15 genes measured were affected by fluoxetine treatment in A/J mice, a strain that does not show a behavioral or neuronal response to fluoxetine.…”

Is it time to reassess the BDNF hypothesis of depression?

“…In addition, antidepressant strategies which do not directly target the monoamine system, such as electroconvulsive shock therapy, transcranial magnetic stimulation, exercise and the novel a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor potentiators and N-methyl-D-aspartic acid (NMDA) antagonists, also increase mRNA or protein BDNF levels in the rat brain. 21,[41][42][43][44][45][46][47][48][49] Although the mechanisms involved in BDNF upregulation remain unknown, SSRI and NARI antidepressants have been reported to increase hippocampal levels of cyclic AMP response binding protein (CREB) in the rat, a nuclear transcription factor known to regulate BDNF expression. 32 …”