title: Impact of actin filament stabilization on adult hippocampal and olfactory bulb neurogenesis.
abstract: Rearrangement of the actin cytoskeleton is essential for dynamic cellular processes. Decreased actin turnover and rigidity of cytoskeletal structures have been associated with aging and cell death. Gelsolin is a Ca(2+)-activated actin-severing protein that is widely expressed throughout the adult mammalian brain. Here, we used gelsolin-deficient (Gsn(-/-)) mice as a model system for actin filament stabilization. In Gsn(-/-) mice, emigration of newly generated cells from the subventricular zone into the olfactory bulb was slowed. In vitro, gelsolin deficiency did not affect proliferation or neuronal differentiation of adult neural progenitors cells (NPCs) but resulted in retarded migration. Surprisingly, hippocampal neurogenesis was robustly induced by gelsolin deficiency. The ability of NPCs to intrinsically sense excitatory activity and thereby implement coupling between network activity and neurogenesis has recently been established. Depolarization-induced [Ca(2+)](i) increases and exocytotic neurotransmitter release were enhanced in Gsn(-/-) synaptosomes. Importantly, treatment of Gsn(-/-) synaptosomes with mycotoxin cytochalasin D, which, like gelsolin, produces actin disassembly, decreased enhanced Ca(2+) influx and subsequent exocytotic norepinephrine release to wild-type levels. Similarly, depolarization-induced glutamate release from Gsn(-/-) brain slices was increased. Furthermore, increased hippocampal neurogenesis in Gsn(-/-) mice was associated with a special microenvironment characterized by enhanced density of perfused vessels, increased regional cerebral blood flow, and increased endothelial nitric oxide synthase (NOS-III) expression in hippocampus. Together, reduced filamentous actin turnover in presynaptic terminals causes increased Ca(2+) influx and, subsequently, elevated exocytotic neurotransmitter release acting on neural progenitors. Increased neurogenesis in Gsn(-/-) hippocampus is associated with a special vascular niche for neurogenesis.
authors.affiliation: Klinik und Poliklinik für Neurologie, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Golo
authors.initials: G
authors.lastname: Kronenberg
authors.forename: Karen
authors.initials: K
authors.lastname: Gertz
authors.forename: Tina
authors.initials: T
authors.lastname: Baldinger
authors.forename: Imke
authors.initials: I
authors.lastname: Kirste
authors.forename: Sarah
authors.initials: S
authors.lastname: Eckart
authors.forename: Ferah
authors.initials: F
authors.lastname: Yildirim
authors.forename: Shengbo
authors.initials: S
authors.lastname: Ji
authors.forename: Isabella
authors.initials: I
authors.lastname: Heuser
authors.forename: Helmut
authors.initials: H
authors.lastname: Schröck
authors.forename: Heide
authors.initials: H
authors.lastname: Hörtnagl
authors.forename: Reinhard
authors.initials: R
authors.lastname: Sohr
authors.forename: Pierre Chryso
authors.initials: PC
authors.lastname: Djoufack
authors.forename: René
authors.initials: R
authors.lastname: Jüttner
authors.forename: Rainer
authors.initials: R
authors.lastname: Glass
authors.forename: Ingo
authors.initials: I
authors.lastname: Przesdzing
authors.forename: Jitender
authors.initials: J
authors.lastname: Kumar
authors.forename: Dorette
authors.initials: D
authors.lastname: Freyer
authors.forename: Rainer
authors.initials: R
authors.lastname: Hellweg
authors.forename: Helmut
authors.initials: H
authors.lastname: Kettenmann
authors.forename: Klaus Benno
authors.initials: KB
authors.lastname: Fink
authors.forename: Matthias
authors.initials: M
authors.lastname: Endres
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism* / Q000648:ultrastructure; D000818:Animals; D020013:Calcium Signaling / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D002560:Cerebrovascular Circulation / Q000502:physiology; D015638:Cytochalasin D / Q000494:pharmacology; D018260:Gelsolin / Q000235:genetics*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D020547:Lateral Ventricles / Q000166:cytology; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000378:metabolism / Q000648:ultrastructure; D009498:Neurotoxins / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D009830:Olfactory Bulb / Q000166:cytology / Q000378:metabolism*; D009924:Organ Culture Techniques; D017729:Presynaptic Terminals / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism* / Q000648:ultrastructure; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
chemical_list: D018260:Gelsolin; D009498:Neurotoxins; D019384:Nucleic Acid Synthesis Inhibitors; D015638:Cytochalasin D; D052250:Nitric Oxide Synthase Type III; D009638:Norepinephrine