ABSTRACT
Electroconvulsive therapy (ECT) is a uniquely effective treatment for major depressive disorder. An increase in hippocampal neurogenesis is implicated in the recovery from depression. We used an inducible genetic mouse model in which only GFAP-expressing stem-like cells (type-1 cells) and their progeny are selectively labeled with the reporter protein ß-galactosidase to track the process of neurogenesis in the dentate gyrus over 3 months following electroconvulsive seizures (ECS), the mouse equivalent of ECT. All ECS protocols tested induced a transient increase in type-1 cell divisions. While this led to an expansion of the type-1 cell pool after high-frequency ECS sessions for 5 consecutive days (5-ECS), asymmetric divisions drove neurogenesis by giving rise to Doublecortin (DCX)-expressing neuroblasts that matured into NeuN+ neurons. Significantly, the increase in newly generated DCX+ and NeuN+ cells after 5-ECS could be traced back to proliferating type-1 cells. Low-frequency continuation ECS (c-ECS) consisting of five single ECS sessions administered every 2 weeks resulted in a similar increase in newborn neurons as the high-frequency 5-ECS protocol. Moreover, the combination of 5-ECS and c-ECS led to a further significant increase in newborn neurons, suggesting a cellular mechanism responsible for the propitious effects of high-frequency ECT followed by continuation ECT in severely depressed patients. The ability of high- and low-frequency ECS to induce normally quiescent type-1 cells to proliferate and generate new neurons sets it apart from other antidepressant treatments and may underlie the superior clinical efficacy of ECT.
Subject(s)
Electroshock/methods , Hippocampus/pathology , Neurons/physiology , Seizures/pathology , Seizures/therapy , Stem Cells/physiology , Animals , Animals, Newborn , Chromosome Mapping , Disease Models, Animal , Doublecortin Domain Proteins , Doublecortin Protein , Doxycycline/administration & dosage , Gene Expression Regulation/physiology , Glial Fibrillary Acidic Protein/genetics , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Mice , Mice, Transgenic , Microtubule-Associated Proteins/metabolism , Mutation/genetics , Neuropeptides/metabolism , Phosphopyruvate Hydratase/metabolism , RNA, Untranslated/genetics , Seizures/etiology , Stem Cells/classificationABSTRACT
In the adult mammalian brain, neurogenesis originates from astrocyte-like stem cells. We generated a transgenic mouse line in which the tetracycline dependent transactivator (tTA) is expressed under the control of the murine GFAP promoter. In this mouse line, inducible gene expression targets virtually all GFAP-expressing stem-like cells in the dentate gyrus and a subset of GFAP-expressing progenitors located primarily in the dorsal wall/dorsolateral corner of the subventricular zone. Outside the neurogenic zones, astrocytes are infrequently targeted. We introduce a panel of transgenic mice which allow both inducible expression of candidate genes under control of the murine GFAP promoter and, at the same time, lineage tracing of all cells descendant from the original GFAP-positive cell. This new mouse line represents a versatile tool for functional analysis of neurogenesis and lineage tracing.
