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D-serine increases adult hippocampal neurogenesis.

Sultan S, Gebara EG, Moullec K, Toni N - Front Neurosci (2013)

Bottom Line: Adult hippocampal neurogenesis results in the continuous formation of new neurons and is a process of brain plasticity involved in learning and memory.Furthermore, D-serine increased the survival of newborn neurons.Together, these results indicate that D-serine treatment resulted in the improvement of several steps of adult neurogenesis in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Fundamental Neurosciences, University of Lausanne Lausanne, Switzerland.

ABSTRACT
Adult hippocampal neurogenesis results in the continuous formation of new neurons and is a process of brain plasticity involved in learning and memory. The neurogenic niche regulates the stem cell proliferation and the differentiation and survival of new neurons and a major contributor to the neurogenic niche are astrocytes. Among the molecules secreted by astrocytes, D-serine is an important gliotransmitter and is a co-agonist of the glutamate, N-methyl-D-aspartate (NMDA) receptor. D-serine has been shown to enhance the proliferation of neural stem cells in vitro, but its effect on adult neurogenesis in vivo is unknown. Here, we tested the effect of exogenous administration of D-serine on adult neurogenesis in the mouse dentate gyrus. We found that 1 week of treatment with D-serine increased cell proliferation in vivo and in vitro and increased the density of neural stem cells and transit amplifying progenitors. Furthermore, D-serine increased the survival of newborn neurons. Together, these results indicate that D-serine treatment resulted in the improvement of several steps of adult neurogenesis in vivo.

No MeSH data available.


Related in: MedlinePlus

D-serine increased cell proliferation in the dentate gyrus. (A) Experimental timeline: Mice were injected intraperitoneally every day with 50 mg/kg of D-serine, for 8 consecutive days. One day after the last injection, mice were pulsed with BrdU (100 mg/kg, 3 injections every 2 h) and, 2 h later, euthanized and prepared for immunohistochemistry. (B) Histogram showing the number of BrdU-expressing cells per dentate gyrus of animals injected with D-serine, NaCl or not injected (Ctrl). Animals: n = 4 per group. (C) Confocal maximal projection micrographs of hippocampal sections immunostained for BrdU in the two injected groups (D-serine and NaCl). Inset: Higher magnification micrograph of a BrdU-expressing cell. (D) Histogram showing the number of Ki-67–expressing cells. Animals: n = 4 per group. (E) Confocal maximal projection micrographs of hippocampal sections immunostained for Ki-67 in the two experimental groups (D-serine and NaCl). Inset: Higher magnification micrograph of Ki-67-expressing cells. Blue: Dapi staining. Each value represents the mean ± SEM; post-hoc bilateral Student's t-test, (***p < 0.001), N.S., non-significant (p > 0.05). Scale bar: 100 μm, insets 10 μm.
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Figure 1: D-serine increased cell proliferation in the dentate gyrus. (A) Experimental timeline: Mice were injected intraperitoneally every day with 50 mg/kg of D-serine, for 8 consecutive days. One day after the last injection, mice were pulsed with BrdU (100 mg/kg, 3 injections every 2 h) and, 2 h later, euthanized and prepared for immunohistochemistry. (B) Histogram showing the number of BrdU-expressing cells per dentate gyrus of animals injected with D-serine, NaCl or not injected (Ctrl). Animals: n = 4 per group. (C) Confocal maximal projection micrographs of hippocampal sections immunostained for BrdU in the two injected groups (D-serine and NaCl). Inset: Higher magnification micrograph of a BrdU-expressing cell. (D) Histogram showing the number of Ki-67–expressing cells. Animals: n = 4 per group. (E) Confocal maximal projection micrographs of hippocampal sections immunostained for Ki-67 in the two experimental groups (D-serine and NaCl). Inset: Higher magnification micrograph of Ki-67-expressing cells. Blue: Dapi staining. Each value represents the mean ± SEM; post-hoc bilateral Student's t-test, (***p < 0.001), N.S., non-significant (p > 0.05). Scale bar: 100 μm, insets 10 μm.

Mentions: We first examined the effect of D-serine on cell proliferation in the dentate gyrus of adult C57Bl/6 mice. Eight-week-old mice were injected with one daily intraperitonal injection of D-serine (50 mg/kg), for 8 days, as this regimen is known to increase extracellular D-serine brain levels (Fukushima et al., 2004; Ferraris et al., 2008) and improve learning performances in mice (Bado et al., 2011; Filali and Lalonde, 2013) (Figure 1A). Control mice were injected with the same volume of the vehicle (0.9% NaCl), or received no injection. One day after the last injection, all mice received 3 intraperitoneal injections of the cell proliferation tracer BrdU (100 mg/kg) at 2-h intervals and were sacrificed 2 h after the last BrdU injection. Brains were sectioned and immunostained for BrdU and the proliferation marker Ki-67 and the number of immunoreactive cells was counted in the granule cell layer of the dentate gyrus. D-serine injections significantly increased the number of BrdU-expressing cells [Figures 1B,C, One-Way ANOVA, F(2, 11) = 20.64, p < 0.001; post-hoc bilateral Student's t-test between groups p < 0.001] and the number of Ki-67-expressing cells [Figures 1D,E, One-Way ANOVA, F(2, 11) = 24.90, p < 0.001; post-hoc bilateral Student's t-test between groups, p < 0.001]. To test whether the D-serine-induced increase in cell proliferation was specific to the dentate gyrus, we counted the number of Ki-67-expressing cells in the S1 area of the somatosensory cortex. D-serine treatment did not change the density of Ki-67+ cells in the somatosensory cortex (NaCl: 2.54 ± 0.14 × 10−6 cells/μ m3 vs. D-serine: 2.83 ± 0.28 × 10−6 cells/μ m3, Student's t-test p = 0.3). No difference was found between non-injected and NaCl-injected animals (post-hoc bilateral Student's t-test p = 0.21 for BrdU+ cells and p = 0.58 for Ki-67+ cells). To test whether the increased number of BrdU- or Ki-67-expressing cells could be caused by a change in hippocampal volume upon D-serine treatment, we measured the volume of the granule cell layer of all mice. We did not detect any difference between treated and control animals [One-Way ANOVA, F(2, 11) = 2.20, p = 0.166, control animals: 0.17 ± 0.006 mm3, animals injected with NaCl 0.18 ± 0.04 mm3, injected with D-serine 0.17 ± 0.03 mm3 respectively, n = 4 animals per group], indicating that the increased numbers of BrdU and Ki-67 cells reflected an increase in cell proliferation.


D-serine increases adult hippocampal neurogenesis.

Sultan S, Gebara EG, Moullec K, Toni N - Front Neurosci (2013)

D-serine increased cell proliferation in the dentate gyrus. (A) Experimental timeline: Mice were injected intraperitoneally every day with 50 mg/kg of D-serine, for 8 consecutive days. One day after the last injection, mice were pulsed with BrdU (100 mg/kg, 3 injections every 2 h) and, 2 h later, euthanized and prepared for immunohistochemistry. (B) Histogram showing the number of BrdU-expressing cells per dentate gyrus of animals injected with D-serine, NaCl or not injected (Ctrl). Animals: n = 4 per group. (C) Confocal maximal projection micrographs of hippocampal sections immunostained for BrdU in the two injected groups (D-serine and NaCl). Inset: Higher magnification micrograph of a BrdU-expressing cell. (D) Histogram showing the number of Ki-67–expressing cells. Animals: n = 4 per group. (E) Confocal maximal projection micrographs of hippocampal sections immunostained for Ki-67 in the two experimental groups (D-serine and NaCl). Inset: Higher magnification micrograph of Ki-67-expressing cells. Blue: Dapi staining. Each value represents the mean ± SEM; post-hoc bilateral Student's t-test, (***p < 0.001), N.S., non-significant (p > 0.05). Scale bar: 100 μm, insets 10 μm.
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Figure 1: D-serine increased cell proliferation in the dentate gyrus. (A) Experimental timeline: Mice were injected intraperitoneally every day with 50 mg/kg of D-serine, for 8 consecutive days. One day after the last injection, mice were pulsed with BrdU (100 mg/kg, 3 injections every 2 h) and, 2 h later, euthanized and prepared for immunohistochemistry. (B) Histogram showing the number of BrdU-expressing cells per dentate gyrus of animals injected with D-serine, NaCl or not injected (Ctrl). Animals: n = 4 per group. (C) Confocal maximal projection micrographs of hippocampal sections immunostained for BrdU in the two injected groups (D-serine and NaCl). Inset: Higher magnification micrograph of a BrdU-expressing cell. (D) Histogram showing the number of Ki-67–expressing cells. Animals: n = 4 per group. (E) Confocal maximal projection micrographs of hippocampal sections immunostained for Ki-67 in the two experimental groups (D-serine and NaCl). Inset: Higher magnification micrograph of Ki-67-expressing cells. Blue: Dapi staining. Each value represents the mean ± SEM; post-hoc bilateral Student's t-test, (***p < 0.001), N.S., non-significant (p > 0.05). Scale bar: 100 μm, insets 10 μm.
Mentions: We first examined the effect of D-serine on cell proliferation in the dentate gyrus of adult C57Bl/6 mice. Eight-week-old mice were injected with one daily intraperitonal injection of D-serine (50 mg/kg), for 8 days, as this regimen is known to increase extracellular D-serine brain levels (Fukushima et al., 2004; Ferraris et al., 2008) and improve learning performances in mice (Bado et al., 2011; Filali and Lalonde, 2013) (Figure 1A). Control mice were injected with the same volume of the vehicle (0.9% NaCl), or received no injection. One day after the last injection, all mice received 3 intraperitoneal injections of the cell proliferation tracer BrdU (100 mg/kg) at 2-h intervals and were sacrificed 2 h after the last BrdU injection. Brains were sectioned and immunostained for BrdU and the proliferation marker Ki-67 and the number of immunoreactive cells was counted in the granule cell layer of the dentate gyrus. D-serine injections significantly increased the number of BrdU-expressing cells [Figures 1B,C, One-Way ANOVA, F(2, 11) = 20.64, p < 0.001; post-hoc bilateral Student's t-test between groups p < 0.001] and the number of Ki-67-expressing cells [Figures 1D,E, One-Way ANOVA, F(2, 11) = 24.90, p < 0.001; post-hoc bilateral Student's t-test between groups, p < 0.001]. To test whether the D-serine-induced increase in cell proliferation was specific to the dentate gyrus, we counted the number of Ki-67-expressing cells in the S1 area of the somatosensory cortex. D-serine treatment did not change the density of Ki-67+ cells in the somatosensory cortex (NaCl: 2.54 ± 0.14 × 10−6 cells/μ m3 vs. D-serine: 2.83 ± 0.28 × 10−6 cells/μ m3, Student's t-test p = 0.3). No difference was found between non-injected and NaCl-injected animals (post-hoc bilateral Student's t-test p = 0.21 for BrdU+ cells and p = 0.58 for Ki-67+ cells). To test whether the increased number of BrdU- or Ki-67-expressing cells could be caused by a change in hippocampal volume upon D-serine treatment, we measured the volume of the granule cell layer of all mice. We did not detect any difference between treated and control animals [One-Way ANOVA, F(2, 11) = 2.20, p = 0.166, control animals: 0.17 ± 0.006 mm3, animals injected with NaCl 0.18 ± 0.04 mm3, injected with D-serine 0.17 ± 0.03 mm3 respectively, n = 4 animals per group], indicating that the increased numbers of BrdU and Ki-67 cells reflected an increase in cell proliferation.

Bottom Line: Adult hippocampal neurogenesis results in the continuous formation of new neurons and is a process of brain plasticity involved in learning and memory.Furthermore, D-serine increased the survival of newborn neurons.Together, these results indicate that D-serine treatment resulted in the improvement of several steps of adult neurogenesis in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Fundamental Neurosciences, University of Lausanne Lausanne, Switzerland.

ABSTRACT
Adult hippocampal neurogenesis results in the continuous formation of new neurons and is a process of brain plasticity involved in learning and memory. The neurogenic niche regulates the stem cell proliferation and the differentiation and survival of new neurons and a major contributor to the neurogenic niche are astrocytes. Among the molecules secreted by astrocytes, D-serine is an important gliotransmitter and is a co-agonist of the glutamate, N-methyl-D-aspartate (NMDA) receptor. D-serine has been shown to enhance the proliferation of neural stem cells in vitro, but its effect on adult neurogenesis in vivo is unknown. Here, we tested the effect of exogenous administration of D-serine on adult neurogenesis in the mouse dentate gyrus. We found that 1 week of treatment with D-serine increased cell proliferation in vivo and in vitro and increased the density of neural stem cells and transit amplifying progenitors. Furthermore, D-serine increased the survival of newborn neurons. Together, these results indicate that D-serine treatment resulted in the improvement of several steps of adult neurogenesis in vivo.

No MeSH data available.


Related in: MedlinePlus