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BDNF-induced recruitment of TrkB receptor into neuronal lipid rafts: roles in synaptic modulation.

Suzuki S, Numakawa T, Shimazu K, Koshimizu H, Hara T, Hatanaka H, Mei L, Lu B, Kojima M - J. Cell Biol. (2004)

Bottom Line: Moreover, disruption of lipid rafts prevented potentiating effects of BDNF on transmitter release in cultured neurons and synaptic response to tetanus in hippocampal slices.In contrast, lipid rafts are not required for BDNF regulation of neuronal survival.Thus, ligand-induced TrkB translocation into lipid rafts may represent a signaling mechanism selective for synaptic modulation by BDNF in the central nervous system.

View Article: PubMed Central - PubMed

Affiliation: Research Institute for Cell Engineering, National Institute for Advanced Industrial Science and Technology, Ikeda, Osaka, Japan.

ABSTRACT
Brain-derived neurotrophic factor (BDNF) plays an important role in synaptic plasticity but the underlying signaling mechanisms remain unknown. Here, we show that BDNF rapidly recruits full-length TrkB (TrkB-FL) receptor into cholesterol-rich lipid rafts from nonraft regions of neuronal plasma membranes. Translocation of TrkB-FL was blocked by Trk inhibitors, suggesting a role of TrkB tyrosine kinase in the translocation. Disruption of lipid rafts by depleting cholesterol from cell surface blocked the ligand-induced translocation. Moreover, disruption of lipid rafts prevented potentiating effects of BDNF on transmitter release in cultured neurons and synaptic response to tetanus in hippocampal slices. In contrast, lipid rafts are not required for BDNF regulation of neuronal survival. Thus, ligand-induced TrkB translocation into lipid rafts may represent a signaling mechanism selective for synaptic modulation by BDNF in the central nervous system.

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Effect of MCD on BDNF modulation of synaptic fatigue at hippocampal CA1 synapses. Neonatal hippocampal slices were pretreated with MCD (2 mM) for 30 min before treatment with BDNF (2 nM) for 1–2 h. A train of HFS (100 Hz, 1 s) was applied to Shaffer collaterals and field EPSPs were recorded from stratum radiatum. The slopes of EPSPs during the entire recording were normalized to the first EPSP slope in each recording. (A) An example of EPSPs elicited by HFS recorded from a BDNF-treated slice. (B) Effect of MCD on synaptic depression induced by HFS. Normalized EPSP slopes in each condition were averaged and plotted against the number of stimulus during HFS. (C) Summary of the MCD effect on the rate of synaptic depression. The plot for each recording was fitted with a single exponential curve, and rate constant (τ) for each condition was averaged and presented. *Indicates significantly higher than all other groups; ANOVA followed by post hoc tests; P < 0.001. The number associated with each column represents the number of slices used for each condition.
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fig7: Effect of MCD on BDNF modulation of synaptic fatigue at hippocampal CA1 synapses. Neonatal hippocampal slices were pretreated with MCD (2 mM) for 30 min before treatment with BDNF (2 nM) for 1–2 h. A train of HFS (100 Hz, 1 s) was applied to Shaffer collaterals and field EPSPs were recorded from stratum radiatum. The slopes of EPSPs during the entire recording were normalized to the first EPSP slope in each recording. (A) An example of EPSPs elicited by HFS recorded from a BDNF-treated slice. (B) Effect of MCD on synaptic depression induced by HFS. Normalized EPSP slopes in each condition were averaged and plotted against the number of stimulus during HFS. (C) Summary of the MCD effect on the rate of synaptic depression. The plot for each recording was fitted with a single exponential curve, and rate constant (τ) for each condition was averaged and presented. *Indicates significantly higher than all other groups; ANOVA followed by post hoc tests; P < 0.001. The number associated with each column represents the number of slices used for each condition.

Mentions: One of the major functions of BDNF in the intact hippocampal synaptic circuits is to attenuate synaptic fatigue induced by a train of high frequency stimulation (HFS; or tetanus, 100 Hz, 1 s; Figurov et al., 1996). We next examined the role of lipid rafts in this form of synaptic modulation. In neonatal hippocampal slices (P12-13) in which the level of endogenous BDNF is low, application of tetanus resulted in pronounced synaptic fatigue at Schaffer collateral-CA1 synapses (Fig. 7 A). Consistent with our previous reports (Figurov et al., 1996), treatment with exogenous BDNF (2 nM) for 1–2 h significantly attenuated the synaptic fatigue (Fig. 7 B). However, pretreatment with MCD for 30 min completely abolished the attenuating effect of BDNF on HFS-induced synaptic fatigue. Quantitative analysis indicated that treatment with BDNF markedly increased the rate constant (τ) for synaptic fatigue and disruption of lipid rafts with MCD completely prevented such an increase (Fig. 7 C). It is important to note that treatment with MCD for 3 h had no effect on synaptic responses to HFS (Fig. 7, B and C), nor did MCD affect basal synaptic transmission or tetanus induced LTP (Ma et al., 2003). These results suggest that short-term exposure to MCD per se does not affect the number of readily releasable vesicles in the presynaptic terminals or the number or properties of AMPA or NMDA receptors on the postsynaptic density.


BDNF-induced recruitment of TrkB receptor into neuronal lipid rafts: roles in synaptic modulation.

Suzuki S, Numakawa T, Shimazu K, Koshimizu H, Hara T, Hatanaka H, Mei L, Lu B, Kojima M - J. Cell Biol. (2004)

Effect of MCD on BDNF modulation of synaptic fatigue at hippocampal CA1 synapses. Neonatal hippocampal slices were pretreated with MCD (2 mM) for 30 min before treatment with BDNF (2 nM) for 1–2 h. A train of HFS (100 Hz, 1 s) was applied to Shaffer collaterals and field EPSPs were recorded from stratum radiatum. The slopes of EPSPs during the entire recording were normalized to the first EPSP slope in each recording. (A) An example of EPSPs elicited by HFS recorded from a BDNF-treated slice. (B) Effect of MCD on synaptic depression induced by HFS. Normalized EPSP slopes in each condition were averaged and plotted against the number of stimulus during HFS. (C) Summary of the MCD effect on the rate of synaptic depression. The plot for each recording was fitted with a single exponential curve, and rate constant (τ) for each condition was averaged and presented. *Indicates significantly higher than all other groups; ANOVA followed by post hoc tests; P < 0.001. The number associated with each column represents the number of slices used for each condition.
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Related In: Results  -  Collection

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fig7: Effect of MCD on BDNF modulation of synaptic fatigue at hippocampal CA1 synapses. Neonatal hippocampal slices were pretreated with MCD (2 mM) for 30 min before treatment with BDNF (2 nM) for 1–2 h. A train of HFS (100 Hz, 1 s) was applied to Shaffer collaterals and field EPSPs were recorded from stratum radiatum. The slopes of EPSPs during the entire recording were normalized to the first EPSP slope in each recording. (A) An example of EPSPs elicited by HFS recorded from a BDNF-treated slice. (B) Effect of MCD on synaptic depression induced by HFS. Normalized EPSP slopes in each condition were averaged and plotted against the number of stimulus during HFS. (C) Summary of the MCD effect on the rate of synaptic depression. The plot for each recording was fitted with a single exponential curve, and rate constant (τ) for each condition was averaged and presented. *Indicates significantly higher than all other groups; ANOVA followed by post hoc tests; P < 0.001. The number associated with each column represents the number of slices used for each condition.
Mentions: One of the major functions of BDNF in the intact hippocampal synaptic circuits is to attenuate synaptic fatigue induced by a train of high frequency stimulation (HFS; or tetanus, 100 Hz, 1 s; Figurov et al., 1996). We next examined the role of lipid rafts in this form of synaptic modulation. In neonatal hippocampal slices (P12-13) in which the level of endogenous BDNF is low, application of tetanus resulted in pronounced synaptic fatigue at Schaffer collateral-CA1 synapses (Fig. 7 A). Consistent with our previous reports (Figurov et al., 1996), treatment with exogenous BDNF (2 nM) for 1–2 h significantly attenuated the synaptic fatigue (Fig. 7 B). However, pretreatment with MCD for 30 min completely abolished the attenuating effect of BDNF on HFS-induced synaptic fatigue. Quantitative analysis indicated that treatment with BDNF markedly increased the rate constant (τ) for synaptic fatigue and disruption of lipid rafts with MCD completely prevented such an increase (Fig. 7 C). It is important to note that treatment with MCD for 3 h had no effect on synaptic responses to HFS (Fig. 7, B and C), nor did MCD affect basal synaptic transmission or tetanus induced LTP (Ma et al., 2003). These results suggest that short-term exposure to MCD per se does not affect the number of readily releasable vesicles in the presynaptic terminals or the number or properties of AMPA or NMDA receptors on the postsynaptic density.

Bottom Line: Moreover, disruption of lipid rafts prevented potentiating effects of BDNF on transmitter release in cultured neurons and synaptic response to tetanus in hippocampal slices.In contrast, lipid rafts are not required for BDNF regulation of neuronal survival.Thus, ligand-induced TrkB translocation into lipid rafts may represent a signaling mechanism selective for synaptic modulation by BDNF in the central nervous system.

View Article: PubMed Central - PubMed

Affiliation: Research Institute for Cell Engineering, National Institute for Advanced Industrial Science and Technology, Ikeda, Osaka, Japan.

ABSTRACT
Brain-derived neurotrophic factor (BDNF) plays an important role in synaptic plasticity but the underlying signaling mechanisms remain unknown. Here, we show that BDNF rapidly recruits full-length TrkB (TrkB-FL) receptor into cholesterol-rich lipid rafts from nonraft regions of neuronal plasma membranes. Translocation of TrkB-FL was blocked by Trk inhibitors, suggesting a role of TrkB tyrosine kinase in the translocation. Disruption of lipid rafts by depleting cholesterol from cell surface blocked the ligand-induced translocation. Moreover, disruption of lipid rafts prevented potentiating effects of BDNF on transmitter release in cultured neurons and synaptic response to tetanus in hippocampal slices. In contrast, lipid rafts are not required for BDNF regulation of neuronal survival. Thus, ligand-induced TrkB translocation into lipid rafts may represent a signaling mechanism selective for synaptic modulation by BDNF in the central nervous system.

Show MeSH
Related in: MedlinePlus