title: Genetic fate mapping of type-1 stem cell-dependent increase in newborn hippocampal neurons after electroconvulsive seizures.
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 β-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.
authors.affiliation: Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, J5, Mannheim, Germany; Department of Molecular Biology, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, J5, Mannheim, Germany; Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, J5, 68159, Germany.
authors.forename: Tillmann
authors.initials: T
authors.lastname: Weber
authors.forename: Vera
authors.initials: V
authors.lastname: Baier
authors.forename: Katharina
authors.initials: K
authors.lastname: Lentz
authors.forename: Elke
authors.initials: E
authors.lastname: Herrmann
authors.forename: Bertram
authors.initials: B
authors.lastname: Krumm
authors.forename: Alexander
authors.initials: A
authors.lastname: Sartorius
authors.forename: Golo
authors.initials: G
authors.lastname: Kronenberg
authors.forename: Dusan
authors.initials: D
authors.lastname: Bartsch
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002874:Chromosome Mapping; D004195:Disease Models, Animal; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D004318:Doxycycline / Q000008:administration & dosage; D004597:Electroshock / Q000379:methods*; D005786:Gene Expression Regulation / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000502:physiology*; D009479:Neuropeptides / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D022661:RNA, Untranslated / Q000235:genetics; D012640:Seizures / Q000209:etiology / Q000473:pathology* / Q000628:therapy*; D013234:Stem Cells / Q000145:classification / Q000502:physiology*
chemical_list: C000714847:Dcx protein, mouse; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D005904:Glial Fibrillary Acidic Protein; C110853:Gt(ROSA)26Sor non-coding RNA, mouse; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D022661:RNA, Untranslated; D049452:Green Fluorescent Proteins; D010751:Phosphopyruvate Hydratase; D004318:Doxycycline
keywords: adult neurogenesis; cell proliferation; electroconvulsive therapy; genetic fate mapping; hippocampus