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Selective survival and maturation of adult-born dentate granule cells expressing the immediate early gene Arc/Arg3.1.

Kuipers SD, Tiron A, Soule J, Messaoudi E, Trentani A, Bramham CR - PLoS ONE (2009)

Bottom Line: Contrary to expectation, LTP did not induce Arc expression in newborn cells at any age, suggesting they might be refractory to synaptically-evoked Arc expression for at least one month.Importantly, however, spontaneous expression of Arc was detected in BrdU-labeled cells and strongly associated with the survival and maturation of NeuN-positive DGCs.These results suggest an unexpected early role for Arc in adult-born DGCs, distinct from its functions in LTP, LTD, and homeostatic synaptic plasticity.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedicine and Bergen Mental Health Research Center, University of Bergen, Bergen, Norway.

ABSTRACT
Progenitor cells in the adult dentate gyrus provide a constant supply of neuronal precursors, yet only a small fraction of these cells survive and develop into mature dentate granule cells (DGCs). A major challenge of current research is thus to understand the stringent selection process that governs the maturation and functional integration of adult-born DGCs. In mature DGCs, high-frequency stimulation (HFS) of the perforant path input elicits robust expression of the immediate early gene Arc/Arg3.1, trafficking of its mRNA to dendrites, and local synthesis of the protein necessary for consolidation of long-term potentiation (LTP). Given the synaptic commitment inherent in LTP consolidation, we considered that HFS-evoked expression of Arc could be used to timemap the functional integration of newborn DGCs. Dividing cells were birthmarked by BrdU-labeling at 1, 7, 14, 21, or 28 days prior to induction of LTP and expression of Arc was examined by confocal microscopy. Contrary to expectation, LTP did not induce Arc expression in newborn cells at any age, suggesting they might be refractory to synaptically-evoked Arc expression for at least one month. Importantly, however, spontaneous expression of Arc was detected in BrdU-labeled cells and strongly associated with the survival and maturation of NeuN-positive DGCs. Moreover, Arc expression at the earliest ages (1 and 7 days), clearly precedes the formation of glutamatergic synapses on new neurons. These results suggest an unexpected early role for Arc in adult-born DGCs, distinct from its functions in LTP, LTD, and homeostatic synaptic plasticity.

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Total BrdU+/Arc+ cells persist with time while BrdU+/Arc− cells subside in the dentate gyrus.a, Graph illustrates the total number of BrdU+/Arc+ and BrdU+/Arc− cells in the GCL. The rise in BrdU+/Arc+ cells in the 14, 21 and 28 day groups compared to days 1 and 7 suggest Arc expression is strongly associated with their survival. b, BrdU+/Arc+ and BrdU+/Arc− cells in the SGZ and c, Hilus represented as total numbers. Total cell numbers represent estimates obtained by multiplying total BrdU cell numbers by respective percentages. d, Number of BrdU+/Arc+ and BrdU+/Arc− cells in the GCL, e, SGZ and f, Hilus depicted as percentages of the total BrdU cell population. Both GCL and SGZ express a similar rise in the percentage of BrdU+/Arc+ cells coupled to a progressive decline in BrdU+/Arc− cells across the ages. The Hilar data show no effects of age but support specificity of the SGZ and GCL findings. The *, #, $, + symbols represents significant effects compared to day 1, 7, 14, 21 respectively. One, two or three symbols represent p<0.05, p<0.005, p<0.0005 respectively.
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pone-0004885-g007: Total BrdU+/Arc+ cells persist with time while BrdU+/Arc− cells subside in the dentate gyrus.a, Graph illustrates the total number of BrdU+/Arc+ and BrdU+/Arc− cells in the GCL. The rise in BrdU+/Arc+ cells in the 14, 21 and 28 day groups compared to days 1 and 7 suggest Arc expression is strongly associated with their survival. b, BrdU+/Arc+ and BrdU+/Arc− cells in the SGZ and c, Hilus represented as total numbers. Total cell numbers represent estimates obtained by multiplying total BrdU cell numbers by respective percentages. d, Number of BrdU+/Arc+ and BrdU+/Arc− cells in the GCL, e, SGZ and f, Hilus depicted as percentages of the total BrdU cell population. Both GCL and SGZ express a similar rise in the percentage of BrdU+/Arc+ cells coupled to a progressive decline in BrdU+/Arc− cells across the ages. The Hilar data show no effects of age but support specificity of the SGZ and GCL findings. The *, #, $, + symbols represents significant effects compared to day 1, 7, 14, 21 respectively. One, two or three symbols represent p<0.05, p<0.005, p<0.0005 respectively.

Mentions: Given the lack of differences in patterns of BrdU+/Arc+ (Fig. 5d,e) as well as BrdU+/Arc− expression (see File S1), data from the ipsilateral and contralateral dentate gyrus were pooled for further analysis (Fig. 7). Interesting time-dependent effects emerged when the Arc-positive and -negative new cells were compared. In the GCL, the total number of BrdU+/Arc− cells decreased (F4,22 = 7.005, p<0.001), while BrdU+/Arc+ cells increased with time (F4,22 = 11.468, p<0.001). Specifically, post-hoc analysis revealed a significant increase in BrdU+/Arc+ cells in the GCL in the 14, 21 and 28 day groups compared to days 1 (14: t = 4.941, p<10−5; 21: t = 5.104, p<10−5 28: t = 4.747, p<10−5) and 7 (14: t = 3.866, p<10−4; 21: t = 4.041, p<10−4 28: t = 3.660, p<10−3) respectively. BrdU+/Arc− cells in the GCL however, were decreased by 21 (t = 3.589, p<10−3) and 28 (t = 5.130, p<10−5) days compared to day 7. Taken together, the results demonstrate a correlation between Arc expression, starting in the youngest newborn cells and survival of these cells in the GCL (Fig. 7a). A similar time-dependent effect was also evident in the SGZ, where the increase in BrdU+/Arc+ (F4,24 = 17.702, p<10−3) was paralleled by a decrease in BrdU+/Arc− cells (F4,24 = 28.838, p<10−3) (Fig. 7b). Specifically, an increase in BrdU+/Arc+ cells was observed in the 14 and 21 day groups compared to days 1 (14: t = 6.065, p<10−6; 21: t = 7.262, p<10−7) and 7 (14: t = 4.249, p<10−4; 21: t = 5.505, p<10−5), while a notable decrease occurred from 21 to 28 days (t = 3.412, p<10−3). Although still higher than day 1 (t = 4.009, p<10−4), levels at 28 days returned to those comparable with day 7, consistent with cell death and/or migration into the GCL. BrdU+/Arc− cells in the SGZ increased by day 7 (t = 2.844, p<10−3) and from there significantly declined by days 14 (t = 4.892, p<10−5), 21 (t = 7.89, p<10−8) and 28 (t = 9.585, p<10−9). Compared to days 1 and 14, levels were significantly reduced by days 21 (1: t = 4.679, p<10−5; 14: t = 2998, p<10−3) and 28 (1: t = 6.295, p<10−6; 14: t = 4.692, p<10−5). The hilus was included in all analyses of Arc to obtain a complete representation of the hippocampus, although it did not show any outstanding results. No time effect was found on the number of BrdU+/Arc+ cells (F4,24 = 0.669, p = 0.620), and only a slight effect was seen in total BrdU+/Arc− cells (F4,24 = 2.909, p = 0.043). Posthoc analysis revealed reduced numbers at 28 days compared to day 1 (t = 3.336, p<10−3) as the only significant difference (Fig. 7c).


Selective survival and maturation of adult-born dentate granule cells expressing the immediate early gene Arc/Arg3.1.

Kuipers SD, Tiron A, Soule J, Messaoudi E, Trentani A, Bramham CR - PLoS ONE (2009)

Total BrdU+/Arc+ cells persist with time while BrdU+/Arc− cells subside in the dentate gyrus.a, Graph illustrates the total number of BrdU+/Arc+ and BrdU+/Arc− cells in the GCL. The rise in BrdU+/Arc+ cells in the 14, 21 and 28 day groups compared to days 1 and 7 suggest Arc expression is strongly associated with their survival. b, BrdU+/Arc+ and BrdU+/Arc− cells in the SGZ and c, Hilus represented as total numbers. Total cell numbers represent estimates obtained by multiplying total BrdU cell numbers by respective percentages. d, Number of BrdU+/Arc+ and BrdU+/Arc− cells in the GCL, e, SGZ and f, Hilus depicted as percentages of the total BrdU cell population. Both GCL and SGZ express a similar rise in the percentage of BrdU+/Arc+ cells coupled to a progressive decline in BrdU+/Arc− cells across the ages. The Hilar data show no effects of age but support specificity of the SGZ and GCL findings. The *, #, $, + symbols represents significant effects compared to day 1, 7, 14, 21 respectively. One, two or three symbols represent p<0.05, p<0.005, p<0.0005 respectively.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2654102&req=5

pone-0004885-g007: Total BrdU+/Arc+ cells persist with time while BrdU+/Arc− cells subside in the dentate gyrus.a, Graph illustrates the total number of BrdU+/Arc+ and BrdU+/Arc− cells in the GCL. The rise in BrdU+/Arc+ cells in the 14, 21 and 28 day groups compared to days 1 and 7 suggest Arc expression is strongly associated with their survival. b, BrdU+/Arc+ and BrdU+/Arc− cells in the SGZ and c, Hilus represented as total numbers. Total cell numbers represent estimates obtained by multiplying total BrdU cell numbers by respective percentages. d, Number of BrdU+/Arc+ and BrdU+/Arc− cells in the GCL, e, SGZ and f, Hilus depicted as percentages of the total BrdU cell population. Both GCL and SGZ express a similar rise in the percentage of BrdU+/Arc+ cells coupled to a progressive decline in BrdU+/Arc− cells across the ages. The Hilar data show no effects of age but support specificity of the SGZ and GCL findings. The *, #, $, + symbols represents significant effects compared to day 1, 7, 14, 21 respectively. One, two or three symbols represent p<0.05, p<0.005, p<0.0005 respectively.
Mentions: Given the lack of differences in patterns of BrdU+/Arc+ (Fig. 5d,e) as well as BrdU+/Arc− expression (see File S1), data from the ipsilateral and contralateral dentate gyrus were pooled for further analysis (Fig. 7). Interesting time-dependent effects emerged when the Arc-positive and -negative new cells were compared. In the GCL, the total number of BrdU+/Arc− cells decreased (F4,22 = 7.005, p<0.001), while BrdU+/Arc+ cells increased with time (F4,22 = 11.468, p<0.001). Specifically, post-hoc analysis revealed a significant increase in BrdU+/Arc+ cells in the GCL in the 14, 21 and 28 day groups compared to days 1 (14: t = 4.941, p<10−5; 21: t = 5.104, p<10−5 28: t = 4.747, p<10−5) and 7 (14: t = 3.866, p<10−4; 21: t = 4.041, p<10−4 28: t = 3.660, p<10−3) respectively. BrdU+/Arc− cells in the GCL however, were decreased by 21 (t = 3.589, p<10−3) and 28 (t = 5.130, p<10−5) days compared to day 7. Taken together, the results demonstrate a correlation between Arc expression, starting in the youngest newborn cells and survival of these cells in the GCL (Fig. 7a). A similar time-dependent effect was also evident in the SGZ, where the increase in BrdU+/Arc+ (F4,24 = 17.702, p<10−3) was paralleled by a decrease in BrdU+/Arc− cells (F4,24 = 28.838, p<10−3) (Fig. 7b). Specifically, an increase in BrdU+/Arc+ cells was observed in the 14 and 21 day groups compared to days 1 (14: t = 6.065, p<10−6; 21: t = 7.262, p<10−7) and 7 (14: t = 4.249, p<10−4; 21: t = 5.505, p<10−5), while a notable decrease occurred from 21 to 28 days (t = 3.412, p<10−3). Although still higher than day 1 (t = 4.009, p<10−4), levels at 28 days returned to those comparable with day 7, consistent with cell death and/or migration into the GCL. BrdU+/Arc− cells in the SGZ increased by day 7 (t = 2.844, p<10−3) and from there significantly declined by days 14 (t = 4.892, p<10−5), 21 (t = 7.89, p<10−8) and 28 (t = 9.585, p<10−9). Compared to days 1 and 14, levels were significantly reduced by days 21 (1: t = 4.679, p<10−5; 14: t = 2998, p<10−3) and 28 (1: t = 6.295, p<10−6; 14: t = 4.692, p<10−5). The hilus was included in all analyses of Arc to obtain a complete representation of the hippocampus, although it did not show any outstanding results. No time effect was found on the number of BrdU+/Arc+ cells (F4,24 = 0.669, p = 0.620), and only a slight effect was seen in total BrdU+/Arc− cells (F4,24 = 2.909, p = 0.043). Posthoc analysis revealed reduced numbers at 28 days compared to day 1 (t = 3.336, p<10−3) as the only significant difference (Fig. 7c).

Bottom Line: Contrary to expectation, LTP did not induce Arc expression in newborn cells at any age, suggesting they might be refractory to synaptically-evoked Arc expression for at least one month.Importantly, however, spontaneous expression of Arc was detected in BrdU-labeled cells and strongly associated with the survival and maturation of NeuN-positive DGCs.These results suggest an unexpected early role for Arc in adult-born DGCs, distinct from its functions in LTP, LTD, and homeostatic synaptic plasticity.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedicine and Bergen Mental Health Research Center, University of Bergen, Bergen, Norway.

ABSTRACT
Progenitor cells in the adult dentate gyrus provide a constant supply of neuronal precursors, yet only a small fraction of these cells survive and develop into mature dentate granule cells (DGCs). A major challenge of current research is thus to understand the stringent selection process that governs the maturation and functional integration of adult-born DGCs. In mature DGCs, high-frequency stimulation (HFS) of the perforant path input elicits robust expression of the immediate early gene Arc/Arg3.1, trafficking of its mRNA to dendrites, and local synthesis of the protein necessary for consolidation of long-term potentiation (LTP). Given the synaptic commitment inherent in LTP consolidation, we considered that HFS-evoked expression of Arc could be used to timemap the functional integration of newborn DGCs. Dividing cells were birthmarked by BrdU-labeling at 1, 7, 14, 21, or 28 days prior to induction of LTP and expression of Arc was examined by confocal microscopy. Contrary to expectation, LTP did not induce Arc expression in newborn cells at any age, suggesting they might be refractory to synaptically-evoked Arc expression for at least one month. Importantly, however, spontaneous expression of Arc was detected in BrdU-labeled cells and strongly associated with the survival and maturation of NeuN-positive DGCs. Moreover, Arc expression at the earliest ages (1 and 7 days), clearly precedes the formation of glutamatergic synapses on new neurons. These results suggest an unexpected early role for Arc in adult-born DGCs, distinct from its functions in LTP, LTD, and homeostatic synaptic plasticity.

Show MeSH
Related in: MedlinePlus