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Mitogen-Activated Protein Kinase Upregulates the Dendritic Translation Machinery in Long-Term Potentiation by Controlling the Mammalian Target of Rapamycin Pathway

Tsokas, Panayiotis, Ma, Tao, Iyengar, Ravi, Landau, Emmanuel M., Blitzer, Robert D.·2007·The Journal of Neuroscience
DOI 10.1523/jneurosci.4548-06.2007
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Abstract

Protein synthesis is required for persistent forms of synaptic plasticity, including long-term potentiation (LTP). A key regulator of LTP-related protein synthesis is mammalian target of rapamycin (mTOR), which is thought to modulate translational capacity by facilitating the synthesis of particular components of the protein synthesis machinery. Recently, extracellularly regulated kinase (ERK) also was shown to mediate plasticity-related translation, an effect that may involve regulation of the mTOR pathway. We studied the interaction between the mTOR and ERK pathways in hippocampal LTP induced at CA3–CA1 synapses by high-frequency synaptic stimulation (HFS). Within minutes after HFS, the expression of multiple translational proteins, the synthesis of which is under the control of mTOR, increased in area CA1 stratum radiatum. This upregulation was detected in pyramidal cell dendrites and was blocked by inhibitors of the ERK pathway. In addition, ERK mediated the stimulation of mTOR by HFS. The possibility that ERK regulates mTOR by acting at a component further upstream in the phosphatidylinositide 3-kinase (PI3K)–mTOR pathway was tested by probing the phosphorylation of p90-S6 kinase, phosphoinositide-dependent kinase 1 (PDK1), and Akt. ERK inhibitors blocked HFS-induced phosphorylation of all three proteins at sites implicated in the regulation of mTOR. Moreover, a component of basal and HFS-induced ERK activity depended on PI3K, indicating that mTOR-mediated protein synthesis in LTP requires coincident and mutually dependent activity in the PI3K and ERK pathways. The role of ERK in regulating PDK1 and Akt, with their extensive effects on cellular function, has important implications for the coordinated response of the neuron to LTP-inducing stimulation.

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CC-BY-NC-SA · From the PDF
Figure 2 ERK activity is required for the upregulation of translational proteins in LTP. A , Immunoblots of CA1 lysates, from slices frozen 30 min after stimulation, showed that the MEK inhibitors PD98059 (50 𝛍 M) and U0126 (20 𝛍 M) prevented the HFS-induced increases in the expression of the TOP mRNA products eEF1A, eEF2, rpS6, and PABP1. The asterisks indicate p < 0.05 compared with control (Con), and sample immunoblots are shown above each summary graph. All group values of n were ≥ 6. B , In the presence of an MEK inhibitor, HFS produced only a decremental potentiation. The rate of decay for slices treated with 50 𝛍 M PD98059 or 20 𝛍 M U0126(bothvalues of n = 5) was similar to that observed previously when protein synthesis or mTOR activity was blocked (Tsokas et al., 2005), whereas LTP was stable for 2 h in vehicletreated controls (Veh) ( n = 5). The traces show superimposed fEPSPs recorded during the baseline period and 2 h after HFS (arrows) in a vehicle-treated control slice (left) and a slice treated with PD98059 (right).
Figure 2 ERK activity is required for the upregulation of translational proteins in LTP. A , Immunoblots of CA1 lysates, from slices frozen 30 min after stimulation, showed that the MEK inhibitors PD98059 (50 𝛍 M) and U0126 (20 𝛍 M) prevented the HFS-induced increases in the expression of the TOP mRNA products eEF1A, eEF2, rpS6, and PABP1. The asterisks indicate p < 0.05 compared with control (Con), and sample immunoblots are shown above each summary graph. All group values of n were ≥ 6. B , In the presence of an MEK inhibitor, HFS produced only a decremental potentiation. The rate of decay for slices treated with 50 𝛍 M PD98059 or 20 𝛍 M U0126(bothvalues of n = 5) was similar to that observed previously when protein synthesis or mTOR activity was blocked (Tsokas et al., 2005), whereas LTP was stable for 2 h in vehicletreated controls (Veh) ( n = 5). The traces show superimposed fEPSPs recorded during the baseline period and 2 h after HFS (arrows) in a vehicle-treated control slice (left) and a slice treated with PD98059 (right).CC-BY-NC-SA · From the PDF
Figure 3 HFS-induced phosphorylation of the mTOR substrate p70S6K is ERK dependent. A , In CA1 regions from slices frozen 30 min after HFS, p70S6K was hyperphosphorylated at the mTOR-dependent site T389 (left) as well as the putative ERK-dependent site T421/S424. Phosphorylation of both sites was blocked by the MEK inhibitor U0126 (20 𝛍 M), whereas 1 𝛍 M rapamycin (Rapa) blocked phosphorylation only at T389. The asterisks indicate p ≤ 0.05 versus controls (Con), with all group values of n ≥ 5. B , After HFS (middle panel), immunoreactivity for phospho(T389)p70S6K was elevated in the apical dendrites and cell bodies of CA1 pyramidal neurons, and diffusely in stratum oriens, compared with vehicle-treated control (Veh) (top panel). Preincubation with 20 𝛍 M U0126 (bottom panel) prevented phosphorylation at T389. Scale bar, 150 𝛍 m. Images are representative of three experiments. C , HFS increased the immunoreactivity for phospho(T421/ S424)-p70S6K (left panels) and for eEF1A (right panels) in dendrites and cell bodies of CA1 pyramidal neurons. The increase in T424/S421-p70S6K phosphorylation was sensitive to U0126 (20 𝛍 M) but not to rapamycin (Rapa; 1 𝛍 M), whereas both inhibitors prevented the HFS-induced rise in eEF1A expression (bottom two images). These images are representative of three independent experiments. Scale bar, 100 𝛍 m.
Figure 3 HFS-induced phosphorylation of the mTOR substrate p70S6K is ERK dependent. A , In CA1 regions from slices frozen 30 min after HFS, p70S6K was hyperphosphorylated at the mTOR-dependent site T389 (left) as well as the putative ERK-dependent site T421/S424. Phosphorylation of both sites was blocked by the MEK inhibitor U0126 (20 𝛍 M), whereas 1 𝛍 M rapamycin (Rapa) blocked phosphorylation only at T389. The asterisks indicate p ≤ 0.05 versus controls (Con), with all group values of n ≥ 5. B , After HFS (middle panel), immunoreactivity for phospho(T389)p70S6K was elevated in the apical dendrites and cell bodies of CA1 pyramidal neurons, and diffusely in stratum oriens, compared with vehicle-treated control (Veh) (top panel). Preincubation with 20 𝛍 M U0126 (bottom panel) prevented phosphorylation at T389. Scale bar, 150 𝛍 m. Images are representative of three experiments. C , HFS increased the immunoreactivity for phospho(T421/ S424)-p70S6K (left panels) and for eEF1A (right panels) in dendrites and cell bodies of CA1 pyramidal neurons. The increase in T424/S421-p70S6K phosphorylation was sensitive to U0126 (20 𝛍 M) but not to rapamycin (Rapa; 1 𝛍 M), whereas both inhibitors prevented the HFS-induced rise in eEF1A expression (bottom two images). These images are representative of three independent experiments. Scale bar, 100 𝛍 m.CC-BY-NC-SA · From the PDF
Figure 4 HFS activates mTOR in an ERK-dependent manner. A , The ERK and mTOR pathways could interact at multiple levels. A schematic of p70S6K phosphorylation sites is shown, with T229 in the catalytic domain, T389 in the linker domain, and T421/S424 in the inhibitory domain, along with the known obligatory phosphorylation sequence. Phosphorylation at T389 is rapamycin-sensitive, whereas ERK mediates phosphorylation at T421/S424, indicating that ERK might control the mTOR-related activation of p70S6K through an intramolecular mechanism. An alternative explanation for the ERK-dependent phosphorylation of T389 is that mTOR activity depends on ERK (dashed line). B , mTOR phosphorylation by HFS requires ERK activity. Immunoblots for phospho(S2448)-mTOR were performed on lysates of CA1 from slices frozen 30 min after stimulation. The HFSinduced phosphorylation at S2448 was blocked in slices treated with 20 𝛍 M U0126. The asterisk indicates p < 0.05 compared with control slices; all values of n ≥ 7. C , HFS causes an ERK-dependent increase in mTOR activity. Slices received either control stimulation in vehicle (Con) or HFS delivered in the presence of vehicle (Veh), 1 𝛍 M rapamycin (Rapa), 20 𝛍 M U0126, or 50 𝛍 M PD98059 (PD). Slices were frozen 10 min after stimulation, and the activity of mTOR purified by immunoprecipitation from CA1 areas was assayed by phosphorylation of recombinant 4EBP1 (detected by immunoblot; see inset, where the arrowhead indicates phospho-4EBP1). The HFS-dependent increase in mTOR activity was completely blocked by the MEK inhibitors, and rapamycin reduced mTOR activity below baseline. The asterisk indicates p < 0.05 compared with control slices; all values of n ≥ 4.
Figure 4 HFS activates mTOR in an ERK-dependent manner. A , The ERK and mTOR pathways could interact at multiple levels. A schematic of p70S6K phosphorylation sites is shown, with T229 in the catalytic domain, T389 in the linker domain, and T421/S424 in the inhibitory domain, along with the known obligatory phosphorylation sequence. Phosphorylation at T389 is rapamycin-sensitive, whereas ERK mediates phosphorylation at T421/S424, indicating that ERK might control the mTOR-related activation of p70S6K through an intramolecular mechanism. An alternative explanation for the ERK-dependent phosphorylation of T389 is that mTOR activity depends on ERK (dashed line). B , mTOR phosphorylation by HFS requires ERK activity. Immunoblots for phospho(S2448)-mTOR were performed on lysates of CA1 from slices frozen 30 min after stimulation. The HFSinduced phosphorylation at S2448 was blocked in slices treated with 20 𝛍 M U0126. The asterisk indicates p < 0.05 compared with control slices; all values of n ≥ 7. C , HFS causes an ERK-dependent increase in mTOR activity. Slices received either control stimulation in vehicle (Con) or HFS delivered in the presence of vehicle (Veh), 1 𝛍 M rapamycin (Rapa), 20 𝛍 M U0126, or 50 𝛍 M PD98059 (PD). Slices were frozen 10 min after stimulation, and the activity of mTOR purified by immunoprecipitation from CA1 areas was assayed by phosphorylation of recombinant 4EBP1 (detected by immunoblot; see inset, where the arrowhead indicates phospho-4EBP1). The HFS-dependent increase in mTOR activity was completely blocked by the MEK inhibitors, and rapamycin reduced mTOR activity below baseline. The asterisk indicates p < 0.05 compared with control slices; all values of n ≥ 4.CC-BY-NC-SA · From the PDF
Figure 5 Reciprocal interactions between ERK and PI3K regulate the mTOR pathway at the level of PDK1. Immunoblots were performed on CA1 regions from slices frozen 5 min after HFS. A , The HFS-induced phosphorylation of PDK1 requires ERK activity. HFS induced the phosphorylation of PDK1 at S241, and this effect was prevented by either 50 𝛍 M PD98059 (PD) or 20 𝛍 M U0126. B , Phosphorylation of Akt at T308 was increased after HFS, and this effect was blocked by preincubation with 50 𝛍 MPD98059(PD). C , The ERK substrate RSK becamehyperphosphorylatedafterHFS,andthiseffectwassensitivetotheMEKinhibitorsU0126(20 𝛍 M) and PD98059 (PD; 50 𝛍 M). All asterisks indicate p < 0.05 versus controls (Con); group values of n ≥ 6. D , PI3K activity mediates a component of MEK/ERK phosphorylation. Incubation with the PI3K inhibitor LY294002 (LY; 20 𝛍 M) reduced both basal and HFS-induced phosphorylation of MEK1/2 at S218/S222 of MEK1 (black bars) and ERK2 at T202/Y204 (gray bars). Data are from excised CA1 regions, and stimulated slices were frozen 5 min after HFS. Sample immunoblots are shown below. Single and double asterisks indicate p < 0.05 and p < 0.01, respectively; all values of n ≥ 4. E , Schematic of the interactions between the ERK and PI3K-mTORpathwaysinregulatingTOPmRNAtranslation,basedontheexperimentssummarizedinFigures1-5.Componentsin black are coregulated by the PI3K and ERK pathways (shown in blue and green, respectively). The arrows do not necessarily represent direct interactions [e.g., the connection between mTOR and p70S6K might involve the inhibition of a protein phosphatase (Peterson et al., 1999)], and some known interactions have been excluded for the sake of clarity (e.g., mTOR facilitates cap-dependent translation by phosphorylating 4EBP).
Figure 5 Reciprocal interactions between ERK and PI3K regulate the mTOR pathway at the level of PDK1. Immunoblots were performed on CA1 regions from slices frozen 5 min after HFS. A , The HFS-induced phosphorylation of PDK1 requires ERK activity. HFS induced the phosphorylation of PDK1 at S241, and this effect was prevented by either 50 𝛍 M PD98059 (PD) or 20 𝛍 M U0126. B , Phosphorylation of Akt at T308 was increased after HFS, and this effect was blocked by preincubation with 50 𝛍 MPD98059(PD). C , The ERK substrate RSK becamehyperphosphorylatedafterHFS,andthiseffectwassensitivetotheMEKinhibitorsU0126(20 𝛍 M) and PD98059 (PD; 50 𝛍 M). All asterisks indicate p < 0.05 versus controls (Con); group values of n ≥ 6. D , PI3K activity mediates a component of MEK/ERK phosphorylation. Incubation with the PI3K inhibitor LY294002 (LY; 20 𝛍 M) reduced both basal and HFS-induced phosphorylation of MEK1/2 at S218/S222 of MEK1 (black bars) and ERK2 at T202/Y204 (gray bars). Data are from excised CA1 regions, and stimulated slices were frozen 5 min after HFS. Sample immunoblots are shown below. Single and double asterisks indicate p < 0.05 and p < 0.01, respectively; all values of n ≥ 4. E , Schematic of the interactions between the ERK and PI3K-mTORpathwaysinregulatingTOPmRNAtranslation,basedontheexperimentssummarizedinFigures1-5.Componentsin black are coregulated by the PI3K and ERK pathways (shown in blue and green, respectively). The arrows do not necessarily represent direct interactions [e.g., the connection between mTOR and p70S6K might involve the inhibition of a protein phosphatase (Peterson et al., 1999)], and some known interactions have been excluded for the sake of clarity (e.g., mTOR facilitates cap-dependent translation by phosphorylating 4EBP).CC-BY-NC-SA · From the PDF

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Metadata

Authors
Tsokas, P., Ma, T., Iyengar, R., Landau, E. M., & Blitzer, R. D.
Venue
The Journal of Neuroscience
Publisher
Society for Neuroscience
Published
2007-05-30
Volume
27
Issue
22
Pages
5885-5894
ISSN
  • 0270-6474
  • 1529-2401
DOI
10.1523/jneurosci.4548-06.2007
Cited by
151
References
3
Language
en
Licence
creativecommons.org/licenses/by-nc-sa/4.0/ (vor, 184 d)

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Tsokas, P., Ma, T., Iyengar, R., Landau, E. M., & Blitzer, R. D. (2007). Mitogen-Activated Protein Kinase Upregulates the Dendritic Translation Machinery in Long-Term Potentiation by Controlling the Mammalian Target of Rapamycin Pathway. The Journal of Neuroscience. https://doi.org/10.1523/jneurosci.4548-06.2007