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 2ϩ -activated actin-severing protein that is widely expressed throughout the adult mammalian brain. Here, we used gelsolin-deficient (Gsn Ϫ/Ϫ ) mice as a model system for actin filament stabilization. In Gsn Ϫ/Ϫ 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 2ϩ ] i increases and exocytotic neurotransmitter release were enhanced in Gsn Ϫ/Ϫ synaptosomes. Importantly, treatment of Gsn Ϫ/Ϫ synaptosomes with mycotoxin cytochalasin D, which, like gelsolin, produces actin disassembly, decreased enhanced Ca 2ϩ influx and subsequent exocytotic norepinephrine release to wild-type levels. Similarly, depolarization-induced glutamate release from Gsn Ϫ/Ϫ brain slices was increased. Furthermore, increased hippocampal neurogenesis in Gsn Ϫ/Ϫ 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 2ϩ influx and, subsequently, elevated exocytotic neurotransmitter release acting on neural progenitors. Increased neurogenesis in Gsn Ϫ/Ϫ hippocampus is associated with a special vascular niche for neurogenesis.

Actin dynamics shape microglia effector functions

“…The increased release of both IL-1beta and IL-18 from activated microglia in the presence of jasplakinolide, therefore, fits well with our earlier finding of increased Ca 2? influx in gelsolin-deficient synaptosomes resulting in enhanced neurotransmitter release (Kronenberg et al 2010). In contrast, synthesis and release of TNFalpha as well as of IL-6 involve the endoplasmic reticulum and the Golgi apparatus.…”

“…Finally, we studied the implications of pathological actin filament stabilization for microglia behaviour in vivo. So far, neuropathological analyses of the brain of Gsn -/-mice have yielded no overt anatomic abnormalities (Endres et al 1999;Yildirim et al 2008;Kronenberg et al 2010). Here, we investigated microglia densities in hippocampus and striatum of adult (\6 months) and aged ([16 months) Gsn ?/?…”

Dendritic spine actin cytoskeleton in autism spectrum disorder

“…The migration of newly generated neuroblasts into the olfactory bulb has been shown to decrease in Gsn −/− mice while the neurogenesis in the hippocampus increases 90 . Moreover, neural progenitor cells derived from Gsn −/− mice show reduced migratory capacity in vitro whereas neuronal differentiation and proliferation kinetics are not affected 90 .…”

Photoperiod affects the cerebrospinal fluid proteome: a comparison between short day– and long day–treated ewes

“…It has also been associated with delayed migration of newly born neural progenitors, as gelsolin-knockout mice display an alteration in the formation of growth cones of neurites [30,31]. We found higher concentrations of gelsolin in the CSF of SD ewes, which may be important for the migration of newly generated neurons.…”