Age-dependent role for Ras-GRF1 in the late stages of adult neurogenesis in the dentate gyrus.
Age-dependent role for Ras-GRF1 in the late stages of adult neurogenesis in the dentate gyrus.
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DOI：
10.1002/hipo.22225
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发表时间：
2014-03
期刊：
影响因子：
3.5
通讯作者：
Feig, Larry A.
中科院分区：
文献类型：
--
作者：
Darcy, Michael J.;Trouche, Stephanie;Jin, Shan-Xue;Feig, Larry A.
海马齿状回在模式分离中起着关键作用，模式分离是进行背景辨别的行为任务所必需的过程。齿状回的一个独特特征是成体神经发生，新生的神经元在神经元电路中扮演着不同的角色。此外，青春期和成年鼠在这一脑区的神经发生功能也不同。在青春期和成年期，不同的信号机制调控成人神经发生的不同步骤仍然知之甚少。我们使用缺乏Ras-GRF1(GRF1)的小鼠来测试GRF1是否在成年神经发生中发挥作用。Ras-GRF1是一种钙依赖的交换因子，调节突触可塑性，并参与小鼠进行的上下文辨别。我们发现Grf1基因敲除小鼠在成年初期(大约2个月大)就开始表现出神经发生缺陷，那时野生型小鼠第一次获得区分密切相关背景的能力。在这个年龄段，Grf1基因敲除小鼠的年轻海马神经元表现出严重的树突树枝减少。到3个月大的时候，新神经元的存活也会受到损害。BrdU标记2个月大的Grf1基因敲除小鼠的新神经元显示，它们在出生后2至3周开始显示存活减少，就在新神经元开始发展复杂的树突形态并过渡到使用谷氨酸能兴奋性输入的时候。有趣的是，当GRF1缺失开始影响神经元功能时，GRF1的表达出现在发育阶段的新神经元中。此外，我们通过将表达针对GRF1的shRNA的逆转录病毒注射到齿状回中，通过下调新神经元中GRF1的表达来诱导类似的新海马神经元的丢失。总之，这些发现表明，在新神经元中表达的GRF1促进了成年神经发生的后期阶段。总体而言，我们的发现表明，GRF1是成年海马神经发生的年龄相关调节因子，这有助于小鼠区分密切相关的背景。
The dentate gyrus of the hippocampus plays a pivotal role in pattern separation, a process required for the behavioral task of contextual discrimination. One unique feature of the dentate gyrus that contributes to pattern separation is adult neurogenesis, where newly born neurons play a distinct role in neuronal circuitry. Moreover, the function of neurogenesis in this brain region differs in adolescent and adult mice. The signaling mechanisms that differentially regulate the distinct steps of adult neurogenesis in adolescence and adulthood remain poorly understood. We used mice lacking RAS-GRF1 (GRF1), a calcium-dependent exchange factor that regulates synaptic plasticity and participates in contextual discrimination performed by mice, to test whether GRF1 plays a role in adult neurogenesis. We show Grf1 knockout mice begin to display a defect in neurogenesis at the onset of adulthood (~2 months of age), when wild-type mice first acquire the ability to distinguish between closely related contexts. At this age, young hippocampal neurons in Grf1 knockout mice display severely reduced dendritic arborization. By 3 months of age, new neuron survival is also impaired. BrdU labeling of new neurons in 2 month-old Grf1 knockout mice shows they begin to display reduced survival between 2 and 3 weeks after birth, just as new neurons begin to develop complex dendritic morphology and transition into using glutamatergic excitatory input. Interestingly, GRF1 expression appears in new neurons at the developmental stage when GRF1 loss begins to effect neuronal function. In addition, we induced a similar loss of new hippocampal neurons by knocking down expression of GRF1 solely in new neurons by injecting retrovirus that express shRNA against GRF1 into the dentate gyrus. Together, these findings show that GRF1 expressed in new neurons promotes late stages of adult neurogenesis. Overall our findings show GRF1 to be an age-dependent regulator of adult hippocampal neurogenesis, which contributes to ability of mice to distinguish closely related contexts.
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DOI：
10.1523/jneurosci.1692-12.2012
发表时间：
2012-06-20
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Kheirbek MA;Tannenholz L;Hen R
通讯作者：
Hen R
影响因子：
2.5
作者：
Brown, JP;Couillard-Després, S;Kuhn, HG
通讯作者：
Kuhn, HG
影响因子：
4.8
作者：
Jin, Shan-Xue;Arai, Junko;Feig, Larry A.
通讯作者：
Feig, Larry A.
影响因子：
25
作者：
Kheirbek, Mazen A.;Klemenhagen, Kristen C.;Sahay, Amar;Hen, Rene
通讯作者：
Hen, Rene
影响因子：
64.8
作者：
ALTMAN, J;DAS, GD
通讯作者：
DAS, GD