Impact of actin filament stabilization on adult hippocampal and olfactory bulb neurogenesis.
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.
Kronenberg
Golo
G
Klinik und Poliklinik für Neurologie, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Gertz
Karen
K
Baldinger
Tina
T
Kirste
Imke
I
Eckart
Sarah
S
Yildirim
Ferah
F
Ji
Shengbo
S
Heuser
Isabella
I
Schröck
Helmut
H
Hörtnagl
Heide
H
Sohr
Reinhard
R
Djoufack
Pierre Chryso
PC
Jüttner
René
R
Glass
Rainer
R
Przesdzing
Ingo
I
Kumar
Jitender
J
Freyer
Dorette
D
Hellweg
Rainer
R
Kettenmann
Helmut
H
Fink
Klaus Benno
KB
Endres
Matthias
M
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
D018260:Gelsolin; D009498:Neurotoxins; D019384:Nucleic Acid Synthesis Inhibitors; D015638:Cytochalasin D; D052250:Nitric Oxide Synthase Type III; D009638:Norepinephrine