Klinik und Poliklinik für Neurologie, Charité-Universitätsmedizin Berlin, Berlin, Germany.
J Neurosci. 2010 Mar 3;30(9):3419-31. doi: 10.1523/JNEUROSCI.4231-09.2010.
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+) 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.
细胞骨架的重排对于动态细胞过程至关重要。细胞骨架结构中肌动蛋白周转率降低和刚性增加与衰老和细胞死亡有关。凝溶胶蛋白是一种广泛表达于成年哺乳动物大脑中的 Ca(2+)-激活的肌动蛋白切割蛋白。在这里，我们使用凝溶胶蛋白缺陷型（Gsn(-/-)）小鼠作为肌动蛋白丝稳定的模型系统。在 Gsn(-/-)小鼠中，从侧脑室区迁移到嗅球的新生成细胞的迁移速度减慢。在体外，凝溶胶蛋白缺陷并不影响成年神经祖细胞（NPC）的增殖或神经元分化，但导致迁移速度减慢。令人惊讶的是，凝溶胶蛋白缺陷强烈诱导海马神经发生。最近已经证实，NPC 具有内在感知兴奋性活动的能力，并因此实现了网络活动与神经发生之间的偶联。Gsn(-/-)突触小体中的去极化诱导的[Ca(2+)]i 增加和胞吐性神经递质释放增强。重要的是，用真菌毒素细胞松弛素 D 处理 Gsn(-/-)突触小体，类似于凝溶胶蛋白，产生肌动蛋白解聚，降低增强的 Ca(2+)内流和随后的胞吐去甲肾上腺素释放至野生型水平。同样，从 Gsn(-/-)脑片中诱导的谷氨酸释放也增加。此外，Gsn(-/-)小鼠中海马神经发生增加与特殊的微环境有关，其特征是灌注血管密度增加、局部脑血流增加和海马内皮型一氧化氮合酶（NOS-III）表达增加。总之，突触前末梢丝状肌动蛋白周转率降低导致 Ca(2+)内流增加，随后引发胞吐性神经递质释放作用于神经祖细胞。Gsn(-/-)海马中的神经发生增加与神经发生的特殊血管龛有关。
