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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+/NeuN+ cells in the dentate gyrus.a, Confocal image of BrdU (green) b, Arc (red) c, NeuN (yellow) d, Merged image illustrating colocalization of BrdU-Arc-NeuN e, Profile measurement of the 3 channels along the indicated line segment verifies colocalization of BrdU-Arc-NeuN in a DGC. Representative images taken from an animal of the 28-day group (195 minutes post HFS). f, Graphs illustrate the percentage of total BrdU+/Arc+ cells which are positive and negative for NeuN in the SGZ and g, GCL. Both regions illustrate a significant and time-dependent increase in NeuN+ cells coupled to a progressive reduction NeuN- indicating that Arc positive new DGCs are neuronal and persist over time. New cells expressed in the GCL by 1 day were negligible. The * and # symbols represent significant effects compared to days 1 and 7 respectively One, two or three symbols represent p<0.05, p<0.005, p<0.0005 respectively.
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pone-0004885-g008: Total BrdU+/Arc+/NeuN+ cells in the dentate gyrus.a, Confocal image of BrdU (green) b, Arc (red) c, NeuN (yellow) d, Merged image illustrating colocalization of BrdU-Arc-NeuN e, Profile measurement of the 3 channels along the indicated line segment verifies colocalization of BrdU-Arc-NeuN in a DGC. Representative images taken from an animal of the 28-day group (195 minutes post HFS). f, Graphs illustrate the percentage of total BrdU+/Arc+ cells which are positive and negative for NeuN in the SGZ and g, GCL. Both regions illustrate a significant and time-dependent increase in NeuN+ cells coupled to a progressive reduction NeuN- indicating that Arc positive new DGCs are neuronal and persist over time. New cells expressed in the GCL by 1 day were negligible. The * and # symbols represent significant effects compared to days 1 and 7 respectively One, two or three symbols represent p<0.05, p<0.005, p<0.0005 respectively.

Mentions: Having found that preferential survival seems to occur in newborn cells positive for Arc expression, we proceeded to explore the nature of this specific subpopulation of BrdU cells by performing a triple labeling for BrdU/Arc/NeuN (Fig. 8a–e). The results demonstrate a significant and time-dependent increase in the BrdU+/Arc+/NeuN+ cells (F4,23 = 29.395, p<10−3) (Fig. 8f) coupled to a progressive reduction in BrdU+/Arc+/NeuN− cells in the SGZ (F4,23 = 29.395, p<10−3) (Fig. 8g). Post-hoc analysis revealed a significant increase in the number of BrdU+/Arc+/NeuN+ cells by 14, 21 and 28 compared to days 1 (14: t = 6.864, p<10−7; 21: t = 7.787, p<10−8; 28: t = 8.017, p<10−8) and 7 (14: t = 5.567, p<10−5; 21: t = 6.577, p<10−6; 28: t = 6.776, p<10−7), with a corresponding reduction of BrdU+/Arc+/NeuN− cells. Likewise, a similar pattern of expression appeared in the GCL, with a significant time-dependent increase in BrdU+/Arc+/NeuN+ cells (F4,11 = 7.761, p<10−3) and decrease in BrdU+/Arc+/NeuN− cells (F4,11 = 4.443, p = 0.022). Post-hoc analysis revealed a significant increase in BrdU+/Arc+/NeuN+ cells by days 14, 21 and 28 compared to days 1 (14: t = 3.865, p<10−3; 21: t = 4.149, p<10−3; 28: t = 3.967, p<10−3) and 7 (21: t = 3.418, p<10−3; 28: t = 3.253, p<10−3), while a significant decrease appeared in BrdU+/Arc+/NeuN− cells by days 21 (t = 3.418, p<10−3) and 28 (t = 3.253, p<10−3) compared to day 7. There were no new cells, positive for Arc, expressed in the GCL after 1 day (irrespective of NeuN expression), giving way to the statistical discrepancy between the otherwise exactly inversely correlated NeuN+ and NeuN− cell populations. Of the entire new DGC population (SGZ and GCL) irrespective of Arc expression, 1.76% (±1.76) assumed the NeuN phenotype by 1 day, 17.6% (±5.6) by 7 days, 62% (±5.7) by 14 days, 74.1% (±5.1) by 21 days and 83.9% (±2.5) by 28 days.


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+/NeuN+ cells in the dentate gyrus.a, Confocal image of BrdU (green) b, Arc (red) c, NeuN (yellow) d, Merged image illustrating colocalization of BrdU-Arc-NeuN e, Profile measurement of the 3 channels along the indicated line segment verifies colocalization of BrdU-Arc-NeuN in a DGC. Representative images taken from an animal of the 28-day group (195 minutes post HFS). f, Graphs illustrate the percentage of total BrdU+/Arc+ cells which are positive and negative for NeuN in the SGZ and g, GCL. Both regions illustrate a significant and time-dependent increase in NeuN+ cells coupled to a progressive reduction NeuN- indicating that Arc positive new DGCs are neuronal and persist over time. New cells expressed in the GCL by 1 day were negligible. The * and # symbols represent significant effects compared to days 1 and 7 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-g008: Total BrdU+/Arc+/NeuN+ cells in the dentate gyrus.a, Confocal image of BrdU (green) b, Arc (red) c, NeuN (yellow) d, Merged image illustrating colocalization of BrdU-Arc-NeuN e, Profile measurement of the 3 channels along the indicated line segment verifies colocalization of BrdU-Arc-NeuN in a DGC. Representative images taken from an animal of the 28-day group (195 minutes post HFS). f, Graphs illustrate the percentage of total BrdU+/Arc+ cells which are positive and negative for NeuN in the SGZ and g, GCL. Both regions illustrate a significant and time-dependent increase in NeuN+ cells coupled to a progressive reduction NeuN- indicating that Arc positive new DGCs are neuronal and persist over time. New cells expressed in the GCL by 1 day were negligible. The * and # symbols represent significant effects compared to days 1 and 7 respectively One, two or three symbols represent p<0.05, p<0.005, p<0.0005 respectively.
Mentions: Having found that preferential survival seems to occur in newborn cells positive for Arc expression, we proceeded to explore the nature of this specific subpopulation of BrdU cells by performing a triple labeling for BrdU/Arc/NeuN (Fig. 8a–e). The results demonstrate a significant and time-dependent increase in the BrdU+/Arc+/NeuN+ cells (F4,23 = 29.395, p<10−3) (Fig. 8f) coupled to a progressive reduction in BrdU+/Arc+/NeuN− cells in the SGZ (F4,23 = 29.395, p<10−3) (Fig. 8g). Post-hoc analysis revealed a significant increase in the number of BrdU+/Arc+/NeuN+ cells by 14, 21 and 28 compared to days 1 (14: t = 6.864, p<10−7; 21: t = 7.787, p<10−8; 28: t = 8.017, p<10−8) and 7 (14: t = 5.567, p<10−5; 21: t = 6.577, p<10−6; 28: t = 6.776, p<10−7), with a corresponding reduction of BrdU+/Arc+/NeuN− cells. Likewise, a similar pattern of expression appeared in the GCL, with a significant time-dependent increase in BrdU+/Arc+/NeuN+ cells (F4,11 = 7.761, p<10−3) and decrease in BrdU+/Arc+/NeuN− cells (F4,11 = 4.443, p = 0.022). Post-hoc analysis revealed a significant increase in BrdU+/Arc+/NeuN+ cells by days 14, 21 and 28 compared to days 1 (14: t = 3.865, p<10−3; 21: t = 4.149, p<10−3; 28: t = 3.967, p<10−3) and 7 (21: t = 3.418, p<10−3; 28: t = 3.253, p<10−3), while a significant decrease appeared in BrdU+/Arc+/NeuN− cells by days 21 (t = 3.418, p<10−3) and 28 (t = 3.253, p<10−3) compared to day 7. There were no new cells, positive for Arc, expressed in the GCL after 1 day (irrespective of NeuN expression), giving way to the statistical discrepancy between the otherwise exactly inversely correlated NeuN+ and NeuN− cell populations. Of the entire new DGC population (SGZ and GCL) irrespective of Arc expression, 1.76% (±1.76) assumed the NeuN phenotype by 1 day, 17.6% (±5.6) by 7 days, 62% (±5.7) by 14 days, 74.1% (±5.1) by 21 days and 83.9% (±2.5) by 28 days.

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