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. 2007 Apr 6;129(1):195-206.
doi: 10.1016/j.cell.2007.01.050.

eIF2alpha phosphorylation bidirectionally regulates the switch from short- to long-term synaptic plasticity and memory

Mauro Costa-Mattioli  1 , Delphine Gobert, Elad Stern, Karine Gamache, Rodney Colina, Claudio Cuello, Wayne Sossin, Randal Kaufman, Jerry Pelletier, Kobi Rosenblum, Kresimir Krnjević, Jean-Claude Lacaille, Karim Nader, Nahum Sonenberg
Affiliations

eIF2alpha phosphorylation bidirectionally regulates the switch from short- to long-term synaptic plasticity and memory

Mauro Costa-Mattioli et al. Cell. .

Abstract

The late phase of long-term potentiation (LTP) and memory (LTM) requires new gene expression, but the molecular mechanisms that underlie these processes are not fully understood. Phosphorylation of eIF2alpha inhibits general translation but selectively stimulates translation of ATF4, a repressor of CREB-mediated late-LTP (L-LTP) and LTM. We used a pharmacogenetic bidirectional approach to examine the role of eIF2alpha phosphorylation in synaptic plasticity and behavioral learning. We show that in eIF2alpha(+/S51A) mice, in which eIF2alpha phosphorylation is reduced, the threshold for eliciting L-LTP in hippocampal slices is lowered, and memory is enhanced. In contrast, only early-LTP is evoked by repeated tetanic stimulation and LTM is impaired, when eIF2alpha phosphorylation is increased by injecting into the hippocampus a small molecule, Sal003, which prevents the dephosphorylation of eIF2alpha. These findings highlight the importance of a single phosphorylation site in eIF2alpha as a key regulator of L-LTP and LTM formation.

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Figures

Figure 1
Figure 1. Late-LTP is induced by single or multiple tetanic trains in hippocampal slices from eIF2α+/S51A mice
A) A single 100 Hz train of stimulation elicits only E-LTP in control slices (open circles), whereas LTP is sustained in eIF2α+/S51A slices (closed circles; at 180 min, p < 0.01). The sustained L-LTP elicited in eIF2α+/S51A slices is suppressed by B) anisomycin (ANISO, closed circles; at 180 min p < 0.05) or C) actinomycin-D (ACTD, closed circles; at 180 min p < 0.01). Horizontal bars indicate the period of incubation with anisomycin and actinomycin-D. D) Similar L-LTP is induced by four tetanic trains in slices from WT and eIF2α+/S51A mice (at 240 min p > 0.05). Data are means ± S.E.M; numbers of tests are indicated. Scale bar 5 ms, 100μV.
Figure 2
Figure 2. Spatial learning is enhanced in eIF2α+/S51A mice
Data (means ± S.E.M.) were obtained either (A, B) in a weak version of the Morris water maze (1 trial per day) or (C, D) in the more intensive, standard version (3 trials per day). A) On day 6, escape latencies, plotted as function of training days, were significantly shorter for eIF2α+/S51A (closed squares, n = 13) as compared to WT mice (open squares, n=14; P < 0.05). B) In the probe test performed after the completion of training, unlike WT mice (open columns, p > 0.05) eIF2α+/S51A mutants (closed columns) showed significant preference for the target quadrant (p < 0.01). C) Escape latencies on day 2 and 3 after a strong training protocol (3 trials per day) show that eIF2α+/S51A mice (n=13) learned significantly faster than control littermates (n=13) (p < 0.05). D) In the first probe test (PT1) performed after three training days, only eIF2α+/S51A mice spent significantly more time in the target quadrant (p < 0.01). E) In the second probe test (PT2), after six days of training, both groups showed a similar preference for the target quadrant (p > 0.05).
Figure 3
Figure 3. Enhanced contextual and auditory fear conditioning in eIF2α+/S51A mice
For contextual fear conditioning, freezing was first assessed during a two min control period in the training context prior to the conditioning (Naïve) and then during a 5 min period 24 hr after training. Freezing in response to the tone was assessed 24 hr after training during a two min period before the tone (pre-CS) and during the tone (CS) presentation. Data (means ± SEM) were obtained after either a weak protocol (single training with weak foot-shock; n=12 for each group; A, B) or a strong protocol (two trainings with stronger foot-shock; n=13 for each group; C, D). When tested 24 hr after training, eIF2α+/S51A mice froze more than the WT controls in response to the context after a weak (A; p<0.001) or a strong (C; p<0.0001) training protocol. They also had an enhanced freezing in response to the tone in both weak (B; p<0.05) and strong (D; p<0.01) protocols.
Figure 4
Figure 4. Long term taste memory and extinction are enhanced in eIF2+/S51A mice
An index > 0.5 means an aversion to, and a score < 0.5 means a preference for, that flavor. A) CTA induced by linking taste of saccharin to LiCl-induced malaise, was similar in eIF2+/S51A (n=5) and WT (n=4) mice (p > 0.05). An index > 0.5 means an aversion to, and a score < 0.5 means a preference for, that flavor. However, pre-exposure to saccharin caused a greater fall in aversion index (latent inhibition (LI)) in eIF2+/S51A mice (p<0.01; eIF2α+/S51A CTA: n=5, eIF2α+/S51A LI: n=7) as compared to WT mice. Further measurements during five days showed a similar decay of CTA with and without LI for WT mice (for all days p>0.05; WT CTA: n=4, WT LI: n=6) (B) and a much accelerated drop after LI in mutants (for all days p<0.01; eIF2α+/S51A CTA: n=5, eIF2α+/S51A LI: n=7), (C). All results are means ± S.E.M.
Figure 5
Figure 5. An inhibitor of eIF2α dephosphorylation (Sal003) prevents the induction of hippocampal L-LTP in slice from WT mice but not in slices from ATF4 -/- mice
A) Mouse embryonic fibroblasts (MEFs) were treated with Sal003 (20 μM) or vehicle (DMSO) and incubated for the indicated periods of time. The phosphorylation state of eIF2α (at serine 51) was determined in cell lysates with a specific polyclonal antibody. B) MEFs were incubated with vehicle or Sal003 (10 μM) for 8 hr and lysates were layered on a 10-ml continuous sucrose gradient (10 to 50%). Polysomes were analyzed as described in Methods. Left, vehicle-treated. Right, Sal003-treated cells. The positions of the polysomes and ribosomes are indicated. C, D) RT-PCR of ATF4 and β-actin mRNAs from separate fractions of sucrose gradients. Sal003 (10 μM) prevents the induction of L-LTP by four trains of tetanic stimulation in slices from WT mice (E; at 240 min, p < 0.05), but not in hippocampal slices from ATF4 -/- mice (F; at 240 min, p > 0.05). Open circles are means (± S.E.M.) from slices treated with vehicle alone and closed circles from slices treated with Sal003 at the times indicated by horizontal bars. Scales represent 5 ms and 100 μV.
Figure 6
Figure 6. Intrahippocampal injection of Sal003 impairs contextual memory
A) Western blots from hippocampal tissue show decreased phosphorylation of eIF2α after contextual fear conditioning. Dorsal hippocampi of rats were removed at different times after training. B) Quantification of normalized p-eIF2α following training (n=4 per time point). C) Diagram of the experimental protocol. Sal003 (40 μM) or Vehicle was infused into the hippocampus immediately after the strong training protocol and dorsal hippocampi were dissected 30 min after training. D) A representative Western blot showing phosphorylation of hippocampal eIF2α after infusion of Sal003. E) Quantification of normalized p- eIF2α using total eIF2α as a loading control (n=4 for vehicle and Sal003 group). F) Diagram of the experimental protocol. Bilateral infusion of Sal003 into the hippocampus immediately after training reduced long-term contextual fear conditioning (G, p < 0.05) but did not affect auditory fear conditioning (H, p > 0.05), both assessed 24 hr after training. Data (means ± S.E.M) from vehicle (n=7) and Sal003-injected rats (n=9) are represented by open and closed columns or symbols, respectively.
Figure 7
Figure 7. A model for control of long-term synaptic plasticity and memory by eIF2α phosphorylation
Under basal conditions, general translation is reduced and ATF4 mRNA translation is augmented, due to partial phosphoryation of eIF2α. As a consequence, expression of synaptic plasticity and memory-related genes is depressed, late-LTP has a high threshold and mnemonic function is poor. Decreased eIF2α phosphorylation reduces ATF4 mRNA translation and enhances general mRNA translation, thus facilitating the induction of gene expression which leads to L-LTP and long-term-memory (LTM) consolidation.
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