Variant brain-derived neurotrophic factor (Val66Met) alters adult olfactory bulb neurogenesis and spontaneous olfactory discrimination
Variant brain-derived neurotrophic factor (Val66Met) alters adult olfactory bulb neurogenesis and spontaneous olfactory discrimination
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DOI：
10.1523/jneurosci.4387-07.2008
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发表时间：
2008-03-05
影响因子：
5.3
通讯作者：
Lee, Francis S.
中科院分区：
文献类型：
--
作者：
Bath, Kevin G.;Mandairon, Nathalie;Lee, Francis S.
神经发生，即新神经元的分裂、迁移和分化，贯穿于整个生命过程。脑源性神经营养因子（BDNF）已被确定为一个潜在的信号分子调节神经发生在脑室下区（SVZ），但其在体内的功能尚未得到很好的定义。我们报告了含有BDNF变异形式[BDNF前结构域66位的缬氨酸（瓦尔）替换为甲硫氨酸（Met）（Val66 Met）]的成年敲入小鼠的新生细胞存活率明显和意想不到的缺陷，该突变显示导致活性依赖性BDNF分泌的选择性损伤。利用敲除小鼠品系，我们确定BDNF和酪氨酸受体激酶B（Trk B）作为观察到的神经发生障碍的关键分子，p75敲除小鼠对细胞增殖或存活没有影响。然后，我们将TrkB的活化形式定位于离散的细胞群体，A型迁移成神经细胞，并证明Val66Met突变小鼠SVZ中TrkB磷酸化减少。有了这些发现，我们确定TrkB信号传导，可能通过BDNF的活性依赖性释放，作为迁移成神经细胞存活的关键步骤。利用一个行为的任务是敏感的中断嗅球神经发生，我们确定了特定的障碍，自发嗅觉歧视，但不是一般的嗅觉敏感性或习惯性的嗅觉刺激BDNF突变小鼠。通过这些观察，我们已经确定了新的联系之间的遗传变异BDNF和成人神经发生在体内，这可能有助于显着损害嗅觉功能。
Neurogenesis, the division, migration, and differentiation of new neurons, occurs throughout life. Brain derived neurotrophic factor (BDNF) has been identified as a potential signaling molecule regulating neurogenesis in the subventricular zone (SVZ), but its functional consequences in vivo have not been well defined. We report marked and unexpected deficits in survival but not proliferation of newly born cells of adult knock-in mice containing a variant form of BDNF [a valine (Val) to methionine (Met) substitution at position 66 in the prodomain of BDNF (Val66Met)], a genetic mutation shown to lead to a selective impairment in activity-dependent BDNF secretion. Utilizing knock-out mouse lines, we identified BDNF and tyrosine receptor kinase B (TrkB) as the critical molecules for the observed impairments in neurogenesis, with p75 knock-out mice showing no effect on cell proliferation or survival. We then localized the activated form of TrkB to a discrete population of cells, type A migrating neuroblasts, and demonstrate a decrease in TrkB phosphorylation in the SVZ of Val66Met mutant mice. With these findings, we identify TrkB signaling, potentially through activity dependent release of BDNF, as a critical step in the survival of migrating neuroblasts. Utilizing a behavioral task shown to be sensitive to disruptions in olfactory bulb neurogenesis, we identified specific impairments in spontaneous olfactory discrimination, but not general olfactory sensitivity or habituation to olfactory stimuli in BDNF mutant mice. Through these observations, we have identified novel links between genetic variant BDNF and adult neurogenesis in vivo, which may contribute to significant impairments in olfactory function.