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. 2010 Nov 23;17(12):627-38.
doi: 10.1101/lm.1974510. Print 2010 Dec.

'Silent' priming of translation-dependent LTP by ß-adrenergic receptors involves phosphorylation and recruitment of AMPA receptors

Gustavo Tenorio  1 , Steven A Connor, Diane Guévremont, Wickliffe C Abraham, Joanna Williams, Thomas J O'Dell, Peter V Nguyen
Affiliations

'Silent' priming of translation-dependent LTP by ß-adrenergic receptors involves phosphorylation and recruitment of AMPA receptors

Gustavo Tenorio et al. Learn Mem. .

Abstract

The capacity for long-term changes in synaptic efficacy can be altered by prior synaptic activity, a process known as "metaplasticity." Activation of receptors for modulatory neurotransmitters can trigger downstream signaling cascades that persist beyond initial receptor activation and may thus have metaplastic effects. Because activation of β-adrenergic receptors (β-ARs) strongly enhances the induction of long-term potentiation (LTP) in the hippocampal CA1 region, we examined whether activation of these receptors also had metaplastic effects on LTP induction. Our results show that activation of β-ARs induces a protein synthesis-dependent form of metaplasticity that primes the future induction of late-phase LTP by a subthreshold stimulus. β-AR activation also induced a long-lasting increase in phosphorylation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) GluA1 subunits at a protein kinase A (PKA) site (S845) and transiently activated extracellular signal-regulated kinase (ERK). Consistent with this, inhibitors of PKA and ERK blocked the metaplastic effects of β-AR activation. β-AR activation also induced a prolonged, translation-dependent increase in cell surface levels of GluA1 subunit-containing AMPA receptors. Our results indicate that β-ARs can modulate hippocampal synaptic plasticity by priming synapses for the future induction of late-phase LTP through up-regulation of translational processes, one consequence of which is the trafficking of AMPARs to the cell surface.

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Figures

Figure 1.
Figure 1.
β-ARs activation induces metaplasticity by reducing the threshold for future LTP induction. (A) ISO application facilitates the induction of LTP (filled diamonds) by subthreshold (HFS: 1 × 100 Hz, 1 sec) stimulation 1 h after washout, whereas HFS stimulation alone results in LTP that decays to baseline in <2 h (open triangles). (B) The metaplastic effect of ISO is temporally limited, as extending the interval between ISO and HFS to 2 h prevented the metaplastic facilitation of LTP. (C) Summary histogram comparing fEPSP slopes obtained 120 min after HFS. Sample traces were taken 10 min after commencement of baseline recordings and 120 min after HFS. Results in C represent means ± SEM; **P < 0.01.
Figure 2.
Figure 2.
β-ARs are required for priming of LTP. (A) Application of the β-AR antagonist propranolol during β-AR activation inhibited metaplasticity (filled triangles). (B) Shifting propranolol application to overlap with HFS did not impair LTP (black diamonds). (C) Summary histogram comparing fEPSP slopes obtained 120 min after HFS. Sample traces were taken 10 min after commencement of baseline recordings and 120 min after HFS. Results in C represent means ± SEM; **P < 0.01.
Figure 3.
Figure 3.
NMDAR activation is required for the induction of β-adrenergic receptor-primed LTP. (A) When the NMDAR antagonist APV was applied during HFS and after prior application of ISO, the metaplastic facilitation of LTP was blocked (open diamonds). Control slices not exposed to APV (black triangles) displayed significantly enhanced expression of LTP compared with APV-treated slices. (B) Summary histogram comparing fEPSP slopes 120 min after HFS. Sample traces were taken 10 min after commencement of baseline recordings and 120 min after HFS. Results in B represent means ± SEM; **P < 0.01.
Figure 4.
Figure 4.
β-AR-dependent metaplasticity generates LTP that is immune to DPT. (A) Application of DPT stimuli (5 Hz, 3 min) 10 min after LTP induction did affect potentiation levels when β-AR are previously activated (black diamonds). Note gradual recovery of fEPSPs to potentiated levels. (B) Summary histogram comparing fEPSP slopes 120 min after HFS. Sample traces were taken 10 min after commencement of baseline recordings and 120 min after HFS stimulation. Results in B represent means ± SEM; **P < 0.01.
Figure 5.
Figure 5.
Translation regulation required for metaplasticity is engaged specifically during β-AR stimulation. (A) Coapplication of ANI with ISO prevented the metaplastic facilitation of LTP (open triangles) when compared with controls not exposed to ANI (black diamonds). (B) Shifting the application of ANI to overlap with HFS (black diamonds) did not impair the metaplastic enhancement of LTP by prior β-AR activation. These results suggest that translation regulation critical for metaplasticity takes place during β-AR stimulation but not during subsequent HFS. (C) Comparisons of fEPSP slopes of these experiments are shown in this summary histogram. (D) A second translation inhibitor, EME similarly prevented the expression of metaplasticity when applied during application of ISO (black diamonds). (E) Summary histogram comparing fEPSP slopes 120 min after HFS. Sample traces were taken 10 min after commencement of baseline recordings and 120 min after HFS stimulation. Results in C and E represent means ± SEM (n = 6); *P < 0.05; **P < 0.01.
Figure 6.
Figure 6.
ERK and PKA are required for β-AR-dependent metaplasticity. (A) U0126, a MEK inhibitor applied during β-AR activation blocked metaplasticity (open triangles). (B) Summary histogram comparing fEPSP slopes 120 min after HFS (n = 6). (C) HFS applied following β-AR activation induced L-LTP (black diamonds), which was blocked in the presence of KT5720 (a PKA inhibitor) overlapping with ISO application (open triangles). (D) Summary histogram for these experiments (n = 6). Sample traces were taken 10 min after commencement of baseline recordings and 120 min after HFS stimulation. Results in B and D represent means ± SEM; **P < 0.01.
Figure 7.
Figure 7.
mTOR is not required for metaplasticity engaged through β-ARs. (A) Application of rapamycin did not inhibit the subsequent induction of LTP generated by HFS 1 h after ISO application (filled squares). (B) Summary histogram comparing fEPSP slopes 120 min after HFS. All sample traces were taken 10 min after commencement of baseline recording and 120 min after stimulation protocol. Results in B represent means ± SEM (n = 6).
Figure 8.
Figure 8.
β-AR activation induces a persistent increase in GluA1 phosphorylation at S845. (A) Slices from the same animal were either untreated (UT) or exposed to 1 µM ISO for 10 min. ISO-treated slices where then collected for analysis either immediately after ISO application or after perfusion with agonist-free aCSF for 60 or 120 min. GluA1 phosphorylation at S845 was significantly elevated compared with untreated controls at all time points tested (*P < 0.05 compared with UT, n = 6). In contrast, ISO had no effect on total GluA1 levels. (B) β-AR activation induced a transient activation of ERK1/2. Although phospho-ERK1/2 levels were significantly increased immediately after ISO application (*P < 0.05 compared with UT), they returned to control levels following ISO washout. Western blots were run using the same samples used for the experiments shown in panel A.
Figure 9.
Figure 9.
ISO treatment increases cell surface GluA1 levels. (Inset) Representative Western blot showing GluA1 levels (∼106 kDa) in cell-surface extracts isolated from ISO, ISO + 100-Hz HFS, ISO + EME, and control slices (n = 7–11). Summary graph showing that ISO induced a protein synthesis-dependent increase in GluA1 cell surface levels relative to the no-drug control, which was not additionally affected by HFS; *P < 0.05.
Figure 10.
Figure 10.
Hypothetical model for primed AMPAR mobility following β-AR activation. β-ARs facilitate AMPAR insertion through PKA-dependent phosphorylation of GluR intracellular C-terminal domains and translation of plasticity related proteins (PRPs), which may include transmembrane AMPAR regulatory proteins (TARPs) that regulate AMPAR trafficking. PKA phosphorylation of S845 on GluA1 and newly synthesized PRPs increase AMPAR expression at extrasynaptic sites. HFS may drive lateral mobilization of AMPARs into the synapse resulting in enhanced synaptic strength.
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