Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2011 Jul;118(1):34-44.
doi: 10.1111/j.1471-4159.2011.07282.x. Epub 2011 May 19.

NMDA receptor regulates migration of newly generated neurons in the adult hippocampus via Disrupted-In-Schizophrenia 1 (DISC1)

Takashi Namba  1 , Guo-Li Ming, Hongjun Song, Chikako Waga, Atsushi Enomoto, Kozo Kaibuchi, Shinichi Kohsaka, Shigeo Uchino
Affiliations

NMDA receptor regulates migration of newly generated neurons in the adult hippocampus via Disrupted-In-Schizophrenia 1 (DISC1)

Takashi Namba et al. J Neurochem. 2011 Jul.

Abstract

In the mammalian brain, new neurons are continuously generated throughout life in the dentate gyrus (DG) of the hippocampus. Previous studies have established that newborn neurons migrate a short distance to be integrated into a pre-existing neuronal circuit in the hippocampus. How the migration of newborn neurons is governed by extracellular signals, however, has not been fully understood. Here, we report that NMDA receptor (NMDA-R)-mediated signaling is essential for the proper migration and positioning of newborn neurons in the DG. An intraperitoneal injection of the NMDA-R antagonists, memantine, or 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) into adult male mice caused the aberrant positioning of newborn neurons, resulting in the overextension of their migration in the DG. Interestingly, we revealed that the administration of NMDA-R antagonists leads to a decrease in the expression of Disrupted-In-Schizophrenia 1 (DISC1), a candidate susceptibility gene for major psychiatric disorders such as schizophrenia, which is also known as a critical regulator of neuronal migration in the DG. Furthermore, the overextended migration of newborn neurons induced by the NMDA-R antagonists was significantly rescued by exogenous expression of DISC1. Collectively, these results suggest that the NMDA-R signaling pathway governs the migration of newborn neurons via the regulation of DISC1 expression in the DG.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1
Administration of NMDA-R antagonist results in the aberrant positioning of Dcx+ immature neurons. (a) Schematic illustration of the experimental design. (b–e) Representative immunohistochemical images of the Dcx+ cells (red) and the NeuN+ cells (white) in control mice (b) and mice injected with memantine (c), CPP (d), or MK-801 (e). (f) Quantitative analysis of the location of the Dcx+ cells in the GCL. (g) Dose-dependent effect of memantine on the positioning of the Dcx+ cells. *p < 0.05, **p < 0.01, ***p < 0.001, NS, not significant. Scale bars = 10 μm.
Fig. 2
Fig. 2
Administration of methamphetamine does not affect the positioning of Dcx+ immature neurons. (a) Schematic illustration of the experimental design. (b and c) Representative immunohistochemical images of the Dcx+ cells (red) and the NeuN+ cells (white) in the control (b) or methamphetamine-injected mice (c). (d) Quantitative analysis of the location of the BrdU+ cells in the GCL. n = 3. Scale bars = 10 μm.
Fig. 3
Fig. 3
Administration of D-cycloserine does not affect the positioning of Dcx+ immature neurons. (a) Schematic illustration of the experimental design. (b and c) Representative immunohistochemical images of the Dcx+ cells (red) and the NeuN+ cells (white) in the control (b) or methamphetamine-injected mice (c). (d) Quantitative analysis of the location of the BrdU+ cells in the GCL. n = 3. Scale bars = 10 μm.
Fig. 4
Fig. 4
Administration of NMDA-R antagonist causes overextended migration of newly generated neurons. (a) Schematic illustration of the experimental design. (b and c) Representative immunostaining images of the BrdU+ cells (red) and the NeuN+ cells (white) in the control (b) or memantine-injected mice (c). Arrows indicate the BrdU+ cells. Scale bars = 10 μm. (d) Quantitative analysis of the location of the BrdU+ cells in the GCL. *p < 0.05.
Fig. 5
Fig. 5
Administration of NMDA-R antagonist does not affect the rate of neuronal differentiation and maturation. (a and b) Representative immunostaining images of BrdU+ cells (red), NeuN+ cells (white), and Dcx+ cells (blue) in the control (a) or memantine-injected mice (b). Scale bars = 10 μm. (c) Quantitative analysis of the percentage of BrdU+ cells, BrdU+/Dcx+ cells, BrdU+/Dcx+/NeuN+ cells, and BrdU+/NeuN+ cells.
Fig. 6
Fig. 6
Administration of NMDA-R antagonists reduces the DISC1 mRNA expression but does not affect NDEL1, Girdin, and LIS1 mRNA expressions in the adult dentate gyrus. (a) Quantitative analysis of the DISC1 mRNA expression in control or memantine-, CPP-, or methamphetamine-injected mice. (b) Quantitative analysis of the DISC1 mRNA expression in control or D-cycloserine-injected mice. (c) Dose-dependent effect of memantine on DISC1 mRNA expression. (d) Quantitative analysis of NDEL1, Girdin, and LIS1 mRNA expressions in control or memantine-injected mice. The ratio of mRNA expression was evaluated using GAPDH as an internal control and real-time PCR. *p < 0.05, **p < 0.01, ***p < 0.001. NS, not significant.
Fig. 7
Fig. 7
The aberrant positioning of Dcx+ cell caused by memantine is partially rescued by lentiviral-mediated DISC1 expression. (a) Schematic illustration of the experimental design. (b–g) Representative immunostaining images of the Dcx+ cells (red), the GFP+ cells (green), and the NeuN+ cells (blue) in the control (b–d) or memantine-injected mice (e–g). Scale bars = 10 μm. (h) Quantitative analysis of the location of the infected or non-infected Dcx+ cells in the GCL. *p < 0.05, **p < 0.01. NS, not significant.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Adachi YU, Watanabe K, Satoh T, Vizi ES. Halothane potentiates the effect of methamphetamine and nomifensine on extracellular dopamine levels in rat striatum: a microdialysis study. Br J Anaesth. 2001;86:837–845. - PubMed
    1. Austin CP, Ky B, Ma L, Morris JA, Shughrue PJ. Expression of Disrupted-In-Schizophrenia-1, a schizophrenia-associated gene, is prominent in the mouse hippocampus throughout brain development. Neuroscience. 2004;124:3–10. - PubMed
    1. Behar TN, Scott CA, Greene CL, Wen X, Smith SV, Maric D, Liu QY, Colton CA, Barker JL. Glutamate acting at NMDA receptors stimulates embryonic cortical neuronal migration. J Neurosci. 1999;19:4449–4461. - PMC - PubMed
    1. Brandon NJ, Handford EJ, Schurov I, et al. Disrupted in Schizophrenia 1 and Nudel form a neurodevelopmentally regulated protein complex: implications for schizophrenia and other major neurological disorders. Mol Cell Neurosci. 2004;25:42–55. - PubMed
    1. Cameron HA, McEwen BS, Gould E. Regulation of adult neurogenesis by excitatory input and NMDA receptor activation in the dentate gyrus. J Neurosci. 1995;15:4687–4692. - PMC - PubMed

Publication types

MeSH terms