Galvão Rui P, Garcia-Verdugo José Manuel, Alvarez-Buylla Arturo
Department of Neurological Surgery and Institute for Regeneration Medicine, University of California at San Francisco, San Francisco, California 94143, USA.
J Neurosci. 2008 Dec 10;28(50):13368-83. doi: 10.1523/JNEUROSCI.2918-08.2008.
In rodents, the adult subventricular zone (SVZ) generates neuroblasts which migrate to the olfactory bulb (OB) and differentiate into interneurons. Recent work suggests that the neurotrophin Brain-Derived Neurotrophic Factor (BDNF) can enhance adult SVZ neurogenesis, but the mechanism by which it acts is unknown. Here, we analyzed the role of BDNF and its receptor TrkB in adult SVZ neurogenesis. We found that TrkB is the most prominent neurotrophin receptor in the mouse SVZ, but only the truncated, kinase-negative isoform (TrkB-TR) was detected. TrkB-TR is expressed in SVZ astrocytes and ependymal cells, but not in neuroblasts. TrkB mutants have reduced SVZ proliferation and survival and fewer new OB neurons. To test whether this effect is cell-autonomous, we grafted SVZ cells from TrkB knock-out mice (TrkB-KO) into the SVZ of wild-type mice (WT). Grafted progenitors generated neuroblasts that migrated to the OB in the absence of TrkB. The survival and differentiation of granular interneurons and Calbindin(+) periglomerular interneurons seemed unaffected by the loss of TrkB, whereas dopaminergic periglomerular neurons were reduced. Intra-ventricular infusion of BDNF yielded different results depending on the animal species, having no effect on neuron production from mouse SVZ, while decreasing it in rats. Interestingly, mice and rats also differ in their expression of the neurotrophin receptor p75. Our results indicate that TrkB is not essential for adult SVZ neurogenesis and do not support the current view that delivering BDNF to the SVZ can enhance adult neurogenesis.
在啮齿动物中，成年脑室下区（SVZ）产生神经母细胞，这些神经母细胞迁移至嗅球（OB）并分化为中间神经元。最近的研究表明，神经营养因子脑源性神经营养因子（BDNF）可增强成年SVZ神经发生，但其作用机制尚不清楚。在此，我们分析了BDNF及其受体TrkB在成年SVZ神经发生中的作用。我们发现TrkB是小鼠SVZ中最突出的神经营养因子受体，但仅检测到截短的、激酶阴性异构体（TrkB-TR）。TrkB-TR在SVZ星形胶质细胞和室管膜细胞中表达，但在神经母细胞中不表达。TrkB突变体的SVZ增殖和存活率降低，新生成的OB神经元减少。为了测试这种效应是否具有细胞自主性，我们将来自TrkB基因敲除小鼠（TrkB-KO）的SVZ细胞移植到野生型小鼠（WT）的SVZ中。移植的祖细胞产生了在没有TrkB的情况下迁移至OB的神经母细胞。颗粒状中间神经元和钙结合蛋白（+）的球周中间神经元的存活和分化似乎不受TrkB缺失的影响，而多巴胺能球周神经元减少。脑室内注入BDNF根据动物种类产生不同结果，对小鼠SVZ的神经元生成没有影响，而在大鼠中则减少。有趣的是，小鼠和大鼠在神经营养因子受体p75的表达上也存在差异。我们的结果表明，TrkB对成年SVZ神经发生并非必不可少，并且不支持目前认为向SVZ递送BDNF可增强成年神经发生的观点。
