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NMDA-receptor-mediated, cell-specific integration of new neurons in adult dentate gyrus

Abstract

New neurons are continuously integrated into existing neural circuits in adult dentate gyrus of the mammalian brain1,2,3,4. Accumulating evidence indicates that these new neurons are involved in learning and memory5,6,7,8. A substantial fraction of newly born neurons die before they mature9,10 and the survival of new neurons is regulated in an experience-dependent manner5,6,11, raising the possibility that the selective survival or death of new neurons has a direct role in a process of learning and memory—such as information storage—through the information-specific construction of new circuits. However, a critical assumption of this hypothesis is that the survival or death decision of new neurons is information-specific. Because neurons receive their information primarily through their input synaptic activity, we investigated whether the survival of new neurons is regulated by input activity in a cell-specific manner. Here we developed a retrovirus-mediated, single-cell gene knockout technique in mice and showed that the survival of new neurons is competitively regulated by their own NMDA-type glutamate receptor during a short, critical period soon after neuronal birth. This finding indicates that the survival of new neurons and the resulting formation of new circuits are regulated in an input-dependent, cell-specific manner. Therefore, the circuits formed by new neurons may represent information associated with input activity within a short time window in the critical period. This information-specific addition of new circuits through selective survival or death of new neurons may be a unique attribute of new neurons that enables them to play a critical role in learning and memory.

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Figure 1: Information-specific formation of new circuits by selective survival/death of new neurons: a hypothesis.
Figure 2: Retrovirus-mediated gene knockout technique.
Figure 3: The absence of functional NMDAR reduces the survival rate of new neurons.
Figure 4: Blockade of NMDAR in surrounding neurons increases the survival of NR1KO new neurons.

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Acknowledgements

We thank M. L. Gage, J. B. Aimone, S. Jessberger and W. Deng for their comments, H. Makino for technical help, S. F. Heinemann for providing mice bred in his colony and S. Tonegawa for his comments and for providing the floxed NR1 mice. A.T. was supported by a research fellowship from the Uehara Memorial Foundation and is supported by the JSPS Postdoctoral Fellowship for Research Abroad; C.Z. was supported by a postdoctoral fellowship from the Epilepsy Foundation through the support of the American Epilepsy Society and the Milken Family Foundation. This work was supported by the Pritzker Neurogenesis Consortium, NIH, a contract through DARPA and The Lookout Foundation. Electron microscopy analysis was conducted at the National Center for Microscopy and Imaging Research, USA.Author contributions A.T. conceived and performed the experiment, analysed the data and wrote the manuscript. V.M.S. performed the electrophysiological experiment. N.T. performed the electron microscopy experiment. C.Z. provided unpublished viral vectors and helped in the construction of a new viral vector. F.H.G. revised the manuscript and obtained the financial support.

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Correspondence to Fred H. Gage.

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Supplementary information

Supplementary Figure 1

Possible activity-dependent mechanisms regulating the survival of new neurons. (JPG 25 kb)

Supplementary Figure 2

A possible competitive mechanism underlying the NMDAR-dependent survival regulation of new neurons. (JPG 31 kb)

Supplementary Legends

Legends for Supplementary Figures 1 and 2 (DOC 20 kb)

Supplementary Methods

Additional description of methods. (DOC 30 kb)

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Tashiro, A., Sandler, V., Toni, N. et al. NMDA-receptor-mediated, cell-specific integration of new neurons in adult dentate gyrus. Nature 442, 929–933 (2006). https://doi.org/10.1038/nature05028

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