Translational control of hippocampal synaptic plasticity and memory by the eIF2α kinase GCN2

Abstract

Studies on various forms of synaptic plasticity have shown a link between messenger RNA translation, learning and memory. Like memory, synaptic plasticity includes an early phase that depends on modification of pre-existing proteins, and a late phase that requires transcription and synthesis of new proteins1,2. Activation of postsynaptic targets seems to trigger the transcription of plasticity-related genes. The new mRNAs are either translated in the soma or transported to synapses before translation. GCN2, a key protein kinase, regulates the initiation of translation. Here we report a unique feature of hippocampal slices from GCN2-/- mice: in CA1, a single 100-Hz train induces a strong and sustained long-term potentiation (late LTP or L-LTP), which is dependent on transcription and translation. In contrast, stimulation that elicits L-LTP in wild-type slices, such as four 100-Hz trains or forskolin, fails to evoke L-LTP in GCN2-/- slices. This aberrant synaptic plasticity is mirrored in the behaviour of GCN2-/- mice in the Morris water maze: after weak training, their spatial memory is enhanced, but it is impaired after more intense training. Activated GCN2 stimulates mRNA translation of ATF4, an antagonist of cyclic-AMP-response-element-binding protein (CREB). Thus, in the hippocampus of GCN2-/- mice, the expression of ATF4 is reduced and CREB activity is increased. Our study provides genetic, physiological, behavioural and molecular evidence that GCN2 regulates synaptic plasticity, as well as learning and memory, through modulation of the ATF4/CREB pathway.

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Figure 1: Unusual properties of LTP induced in slices from GCN2 -/- mice.
Figure 2: ATF4 mRNA translation is downregulated in GCN2 -/- mice.
Figure 3: GCN2 -/- mice are impaired in contextual but not auditory fear conditioning.
Figure 4: Long-term spatial memory of GCN2 -/- mice is enhanced after weak training but impaired after more intense training (in the Morris water maze).

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Acknowledgements

We thank E. Kandel, K. Krnjević, K. Rosenblum, E. Landau, R. Blitzer, C. Alberini, Y. Mamane and T. Lubell for comments on the manuscript; Y. Zhang, R. Jungreis and A. Sylvestre for assisting in the production and maintenance of the GCN2-/- mice; and Colin Lister for assistance. This work was supported by grants from the Canadian Institute of Health Research (CIHR) and the Howard Hughes Medical Institute (HHMI) to N.S, a CIHR Group Grant to J.-C.L and W.S; a CIHR grant to N. Seidah; an NIH grant to D.R.; CIHR, Natural Sciences and Engineering Research Council of Canada (NSERC), Volkswagen Foundation and EJLB Foundation grants to K.N.; and a CIHR grant to A.C.C. N.S. is a CIHR Distinguished Scientist and a HHMI International scholar. M.C.-M. is supported by a CIHR postdoctoral fellowship.

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Correspondence to Nahum Sonenberg.

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Supplementary information

Supplementary Notes

This contains the Supplementary Material and Supplementary Methods, Supplementary Results, Supplementary Discussion and Supplementary Figure Legends. (DOC 64 kb)

Supplementary Figure S1

Generation and characterization of the GCN2-/- mice. (PDF 98 kb)

Supplementary Figure S2

Expression of GCN2 in adult brain. (PDF 140 kb)

Supplementary Figure S3

Lack of gross structural abnormalities in GCN2-/- mice. (PDF 93 kb)

Supplementary Figure S4

Normal basal synaptic transmission in GCN2 -/- mice. (PDF 1365 kb)

Supplementary Figure S5

Properties of LTP induced in slices from GCN2-/- mice. (PDF 3183 kb)

Supplementary Figure S6

LTD is normal in GCN2 -/-slices. (PDF 1565 kb)

Supplementary Figure S7

L-LTP but not E-LTP-inducing protocols regulate GCN2 activity. (PDF 217 kb)

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Costa-Mattioli, M., Gobert, D., Harding, H. et al. Translational control of hippocampal synaptic plasticity and memory by the eIF2α kinase GCN2. Nature 436, 1166–1170 (2005). https://doi.org/10.1038/nature03897

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