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Involvement of TrkB- and p75(NTR)-signaling pathways in two contrasting forms of long-lasting synaptic plasticity.

Sakuragi S, Tominaga-Yoshino K, Ogura A - Sci Rep (2013)

Bottom Line: However, the cellular mechanisms underlying this repetition-dependent consolidation of memory remain unclear.We proposed these phenomena as useful in vitro models for analyzing repetition-dependent consolidation.These results suggest the alternative activation of the p75(NTR) pathway by BDNF under TrkB-masking conditions and of the TrkB pathway by proBDNF under p75(NTR)-masking conditions, thus supporting the aforementioned hypothesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, Osaka University Graduate School of Frontier Biosciences, Suita 565-0871 Osaka, Japan.

ABSTRACT
The repetition of experience is often necessary to establish long-lasting memory. However, the cellular mechanisms underlying this repetition-dependent consolidation of memory remain unclear. We previously observed in organotypic slice cultures of the rodent hippocampus that repeated inductions of long-term potentiation (LTP) led to a slowly developing long-lasting synaptic enhancement coupled with synaptogenesis. We also reported that repeated inductions of long-term depression (LTD) produced a long-lasting synaptic suppression coupled with synapse elimination. We proposed these phenomena as useful in vitro models for analyzing repetition-dependent consolidation. Here, we hypothesized that the enhancement and suppression are mediated by the brain-derived neurotrophic factor (BDNF)-TrkB signaling pathway and the proBDNF-p75(NTR) pathway, respectively. When we masked the respective pathways, reversals of the enhancement and suppression resulted. These results suggest the alternative activation of the p75(NTR) pathway by BDNF under TrkB-masking conditions and of the TrkB pathway by proBDNF under p75(NTR)-masking conditions, thus supporting the aforementioned hypothesis.

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Prolonged application of the anti-p75NTR antibody during repetitive inductions of LTD leads to a reversal of synaptic suppression.(a) Timeline of the experimental procedures. (b) The synaptic strength, as indicated by the maximal fEPSP, is shown together with representative recordings. The numbers of slices examined are 16 for control (3 × mock), 17 for 3 × DHPG, 8 for 3 × DHPG + anti-p75NTR and 13 for 3 × DHPG + anti-p75NTR + anti-TrkB. The scale bars are 10 msec (horizontal) and 1 mV (vertical). (c) The dendritic spine density is shown together with representative images of the dendritic segments. The numbers of segments [slices] examined are 38 [8] for control, 36 [9] for 3 × DHPG, 20 [5] for 3 × DHPG + anti-p75NTR and 40 [9] for 3 × DHPG + anti-p75NTR + anti-TrkB. The scale bar indicates 2 μm. (d, e) The immunoblotting analysis, supporting the alternative activation of TrkB by proBDNF under p75NTR-masking conditions. Lysates were prepared 3 hours after the third LTD induction. Five slices were pooled for preparing 1 sample (d). Two bands that are immunopositive to the anti-TrkB antibody are full-length (FL-) and truncated (Trunc-) forms of TrkB47. The bands are taken out from a single membrane. (For original images of the membrane, see Supplementary Fig. S4 on line). The quantified levels of phosphorylated Trk, total full-length TrkB and p75NTR are shown in (e). The analysis was repeated 8 times (4 times for p75NTR), the density of each band was relativized to that of control (3 × mock) for each time, and the mean values are plotted here. The P values are 0.016 for *1, 7.12 × 10−4 for ***2, 1.00 × 10−7 for ***3, 0.019 for *4, 0.0015 for **5, 0.025 for *6, 0.0029 for **7, 1.66 × 10−7 for ***8, 0.0087 for **9, 0.0063 for **10 and 0.0032 for **11.
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f4: Prolonged application of the anti-p75NTR antibody during repetitive inductions of LTD leads to a reversal of synaptic suppression.(a) Timeline of the experimental procedures. (b) The synaptic strength, as indicated by the maximal fEPSP, is shown together with representative recordings. The numbers of slices examined are 16 for control (3 × mock), 17 for 3 × DHPG, 8 for 3 × DHPG + anti-p75NTR and 13 for 3 × DHPG + anti-p75NTR + anti-TrkB. The scale bars are 10 msec (horizontal) and 1 mV (vertical). (c) The dendritic spine density is shown together with representative images of the dendritic segments. The numbers of segments [slices] examined are 38 [8] for control, 36 [9] for 3 × DHPG, 20 [5] for 3 × DHPG + anti-p75NTR and 40 [9] for 3 × DHPG + anti-p75NTR + anti-TrkB. The scale bar indicates 2 μm. (d, e) The immunoblotting analysis, supporting the alternative activation of TrkB by proBDNF under p75NTR-masking conditions. Lysates were prepared 3 hours after the third LTD induction. Five slices were pooled for preparing 1 sample (d). Two bands that are immunopositive to the anti-TrkB antibody are full-length (FL-) and truncated (Trunc-) forms of TrkB47. The bands are taken out from a single membrane. (For original images of the membrane, see Supplementary Fig. S4 on line). The quantified levels of phosphorylated Trk, total full-length TrkB and p75NTR are shown in (e). The analysis was repeated 8 times (4 times for p75NTR), the density of each band was relativized to that of control (3 × mock) for each time, and the mean values are plotted here. The P values are 0.016 for *1, 7.12 × 10−4 for ***2, 1.00 × 10−7 for ***3, 0.019 for *4, 0.0015 for **5, 0.025 for *6, 0.0029 for **7, 1.66 × 10−7 for ***8, 0.0087 for **9, 0.0063 for **10 and 0.0032 for **11.

Mentions: Thereon we performed a symmetrical examination: what would be the result if a LOSS-producing stimulus (3 repeated inductions of chemical LTD) was given when p75NTR was masked during all 3 LTD inductions. As shown in Fig. 4a–c, the prolonged masking of p75NTR by the antip75NTR antibody did not result in a simple inhibition of LOSS establishment but instead resulted in an apparent reversal from LOSS to RISE. This result was explained by the alternative activations of TrkB by proBDNF when p75NTR was masked chronically. When both TrkB and p75NTR were masked, the LOSS-producing stimulus produced neither RISE nor LOSS.


Involvement of TrkB- and p75(NTR)-signaling pathways in two contrasting forms of long-lasting synaptic plasticity.

Sakuragi S, Tominaga-Yoshino K, Ogura A - Sci Rep (2013)

Prolonged application of the anti-p75NTR antibody during repetitive inductions of LTD leads to a reversal of synaptic suppression.(a) Timeline of the experimental procedures. (b) The synaptic strength, as indicated by the maximal fEPSP, is shown together with representative recordings. The numbers of slices examined are 16 for control (3 × mock), 17 for 3 × DHPG, 8 for 3 × DHPG + anti-p75NTR and 13 for 3 × DHPG + anti-p75NTR + anti-TrkB. The scale bars are 10 msec (horizontal) and 1 mV (vertical). (c) The dendritic spine density is shown together with representative images of the dendritic segments. The numbers of segments [slices] examined are 38 [8] for control, 36 [9] for 3 × DHPG, 20 [5] for 3 × DHPG + anti-p75NTR and 40 [9] for 3 × DHPG + anti-p75NTR + anti-TrkB. The scale bar indicates 2 μm. (d, e) The immunoblotting analysis, supporting the alternative activation of TrkB by proBDNF under p75NTR-masking conditions. Lysates were prepared 3 hours after the third LTD induction. Five slices were pooled for preparing 1 sample (d). Two bands that are immunopositive to the anti-TrkB antibody are full-length (FL-) and truncated (Trunc-) forms of TrkB47. The bands are taken out from a single membrane. (For original images of the membrane, see Supplementary Fig. S4 on line). The quantified levels of phosphorylated Trk, total full-length TrkB and p75NTR are shown in (e). The analysis was repeated 8 times (4 times for p75NTR), the density of each band was relativized to that of control (3 × mock) for each time, and the mean values are plotted here. The P values are 0.016 for *1, 7.12 × 10−4 for ***2, 1.00 × 10−7 for ***3, 0.019 for *4, 0.0015 for **5, 0.025 for *6, 0.0029 for **7, 1.66 × 10−7 for ***8, 0.0087 for **9, 0.0063 for **10 and 0.0032 for **11.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3822391&req=5

f4: Prolonged application of the anti-p75NTR antibody during repetitive inductions of LTD leads to a reversal of synaptic suppression.(a) Timeline of the experimental procedures. (b) The synaptic strength, as indicated by the maximal fEPSP, is shown together with representative recordings. The numbers of slices examined are 16 for control (3 × mock), 17 for 3 × DHPG, 8 for 3 × DHPG + anti-p75NTR and 13 for 3 × DHPG + anti-p75NTR + anti-TrkB. The scale bars are 10 msec (horizontal) and 1 mV (vertical). (c) The dendritic spine density is shown together with representative images of the dendritic segments. The numbers of segments [slices] examined are 38 [8] for control, 36 [9] for 3 × DHPG, 20 [5] for 3 × DHPG + anti-p75NTR and 40 [9] for 3 × DHPG + anti-p75NTR + anti-TrkB. The scale bar indicates 2 μm. (d, e) The immunoblotting analysis, supporting the alternative activation of TrkB by proBDNF under p75NTR-masking conditions. Lysates were prepared 3 hours after the third LTD induction. Five slices were pooled for preparing 1 sample (d). Two bands that are immunopositive to the anti-TrkB antibody are full-length (FL-) and truncated (Trunc-) forms of TrkB47. The bands are taken out from a single membrane. (For original images of the membrane, see Supplementary Fig. S4 on line). The quantified levels of phosphorylated Trk, total full-length TrkB and p75NTR are shown in (e). The analysis was repeated 8 times (4 times for p75NTR), the density of each band was relativized to that of control (3 × mock) for each time, and the mean values are plotted here. The P values are 0.016 for *1, 7.12 × 10−4 for ***2, 1.00 × 10−7 for ***3, 0.019 for *4, 0.0015 for **5, 0.025 for *6, 0.0029 for **7, 1.66 × 10−7 for ***8, 0.0087 for **9, 0.0063 for **10 and 0.0032 for **11.
Mentions: Thereon we performed a symmetrical examination: what would be the result if a LOSS-producing stimulus (3 repeated inductions of chemical LTD) was given when p75NTR was masked during all 3 LTD inductions. As shown in Fig. 4a–c, the prolonged masking of p75NTR by the antip75NTR antibody did not result in a simple inhibition of LOSS establishment but instead resulted in an apparent reversal from LOSS to RISE. This result was explained by the alternative activations of TrkB by proBDNF when p75NTR was masked chronically. When both TrkB and p75NTR were masked, the LOSS-producing stimulus produced neither RISE nor LOSS.

Bottom Line: However, the cellular mechanisms underlying this repetition-dependent consolidation of memory remain unclear.We proposed these phenomena as useful in vitro models for analyzing repetition-dependent consolidation.These results suggest the alternative activation of the p75(NTR) pathway by BDNF under TrkB-masking conditions and of the TrkB pathway by proBDNF under p75(NTR)-masking conditions, thus supporting the aforementioned hypothesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, Osaka University Graduate School of Frontier Biosciences, Suita 565-0871 Osaka, Japan.

ABSTRACT
The repetition of experience is often necessary to establish long-lasting memory. However, the cellular mechanisms underlying this repetition-dependent consolidation of memory remain unclear. We previously observed in organotypic slice cultures of the rodent hippocampus that repeated inductions of long-term potentiation (LTP) led to a slowly developing long-lasting synaptic enhancement coupled with synaptogenesis. We also reported that repeated inductions of long-term depression (LTD) produced a long-lasting synaptic suppression coupled with synapse elimination. We proposed these phenomena as useful in vitro models for analyzing repetition-dependent consolidation. Here, we hypothesized that the enhancement and suppression are mediated by the brain-derived neurotrophic factor (BDNF)-TrkB signaling pathway and the proBDNF-p75(NTR) pathway, respectively. When we masked the respective pathways, reversals of the enhancement and suppression resulted. These results suggest the alternative activation of the p75(NTR) pathway by BDNF under TrkB-masking conditions and of the TrkB pathway by proBDNF under p75(NTR)-masking conditions, thus supporting the aforementioned hypothesis.

Show MeSH
Related in: MedlinePlus