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.
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Kandel, E. R. The molecular biology of memory storage: a dialogue between genes and synapses. Science 294, 1030–1038 (2001)
McGaugh, J. L. Memory–a century of consolidation. Science 287, 248–251 (2000)
Mathews, M. B., Sonenberg, N. & Hershey, J. W. B. in Translational Control of Gene Expression (eds Sonenberg, N., Hershey, J. W. B. & Matthews, M. B.) 1–33 (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 2000)
Hinnebusch, A. G. in Translational Control of Gene Expression (eds Sonenberg, N., Hershey, J. W. B. & Matthews, M. B.) 185–244 (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 2000)
Sonenberg, N. & Dever, T. E. Eukaryotic translation initiation factors and regulators. Curr. Opin. Struct. Biol. 13, 56–63 (2003)
Harding, H. P. et al. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol. Cell 6, 1099–1108 (2000)
Yin, J. C. et al. Induction of a dominant negative CREB transgene specifically blocks long-term memory in Drosophila. Cell 79, 49–58 (1994)
Bartsch, D. et al. Aplysia CREB2 represses long-term facilitation: relief of repression converts transient facilitation into long-term functional and structural change. Cell 83, 979–992 (1995)
Abel, T., Martin, K. C., Bartsch, D. & Kandel, E. R. Memory suppressor genes: inhibitory constraints on the storage of long-term memory. Science 279, 338–341 (1998)
Chen, A. et al. Inducible enhancement of memory storage and synaptic plasticity in transgenic mice expressing an inhibitor of ATF4 (CREB-2) and C/EBP proteins. Neuron 39, 655–669 (2003)
Vattem, K. M. & Wek, R. C. Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells. Proc. Natl Acad. Sci. USA 101, 11269–11274 (2004)
Scheuner, D. et al. Translational control is required for the unfolded protein response and in vivo glucose homeostasis. Mol. Cell 7, 1165–1176 (2001)
Santoyo, J., Alcalde, J., Mendez, R., Pulido, D. & de Haro, C. Cloning and characterization of a cDNA encoding a protein synthesis initiation factor-2α (eIF-2α) kinase from Drosophila melanogaster. Homology to yeast GCN2 protein kinase. J. Biol. Chem. 272, 12544–12550 (1997)
Berlanga, J. J., Santoyo, J. & De Haro, C. Characterization of a mammalian homolog of the GCN2 eukaryotic initiation factor 2α kinase. Eur. J. Biochem. 265, 754–762 (1999)
Sood, R., Porter, A. C., Olsen, D. A., Cavener, D. R. & Wek, R. C. A mammalian homologue of GCN2 protein kinase important for translational control by phosphorylation of eukaryotic initiation factor-2α. Genetics 154, 787–801 (2000)
Frey, U. & Morris, R. G. Synaptic tagging and long-term potentiation. Nature 385, 533–536 (1997)
Kelleher, R. J. III, Govindarajan, A., Jung, H. Y., Kang, H. & Tonegawa, S. Translational control by MAPK signalling in long-term synaptic plasticity and memory. Cell 116, 467–479 (2004)
Huang, Y. Y. & Kandel, E. R. D1/D5 receptor agonists induce a protein synthesis-dependent late potentiation in the CA1 region of the hippocampus. Proc. Natl Acad. Sci. USA 92, 2446–2450 (1995)
Palmer, M. J., Irving, A. J., Seabrook, G. R., Jane, D. E. & Collingridge, G. L. The group I mGlu receptor agonist DHPG induces a novel form of LTD in the CA1 region of the hippocampus. Neuropharmacology 36, 1517–1532 (1997)
Impey, S. et al. Induction of CRE-mediated gene expression by stimuli that generate long-lasting LTP in area CA1 of the hippocampus. Neuron 16, 973–982 (1996)
LeDoux, J. E. Emotion circuits in the brain. Annu. Rev. Neurosci. 23, 155–184 (2000)
Morris, R. G., Garrud, P., Rawlins, J. N. & O'Keefe, J. Place navigation impaired in rats with hippocampal lesions. Nature 297, 681–683 (1982)
Barco, A., Alarcon, J. M. & Kandel, E. R. Expression of constitutively active CREB protein facilitates the late phase of long-term potentiation by enhancing synaptic capture. Cell 108, 689–703 (2002)
Malleret, G. et al. Inducible and reversible enhancement of learning, memory, and long-term potentiation by genetic inhibition of calcineurin. Cell 104, 675–686 (2001)
Chen, C. Y. & Shyu, A. B. Selective degradation of early-response-gene mRNAs: functional analyses of sequence features of the AU-rich elements. Mol. Cell. Biol. 14, 8471–8482 (1994)
Shyu, A. B., Greenberg, M. E. & Belasco, J. G. The c-fos transcript is targeted for rapid decay by two distinct mRNA degradation pathways. Genes Dev. 3, 60–72 (1989)
Seidah, N. G. et al. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc. Natl Acad. Sci. USA 100, 928–933 (2003)
Lapointe, V. et al. Synapse-specific mGluR1-dependent long-term potentiation in interneurones regulates mouse hippocampal inhibition. J. Physiol. (Lond.) 555, 125–135 (2004)
Chan, J., Khan, S. N., Harvey, I., Merrick, W. & Pelletier, J. Eukaryotic protein synthesis inhibitors identified by comparison of cytotoxicity profiles. RNA 10, 528–543 (2004)
Saura, C. A. et al. Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration. Neuron 42, 23–36 (2004)
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.
Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.
This contains the Supplementary Material and Supplementary Methods, Supplementary Results, Supplementary Discussion and Supplementary Figure Legends. (DOC 64 kb)
Generation and characterization of the GCN2-/- mice. (PDF 98 kb)
Expression of GCN2 in adult brain. (PDF 140 kb)
Lack of gross structural abnormalities in GCN2-/- mice. (PDF 93 kb)
Normal basal synaptic transmission in GCN2 -/- mice. (PDF 1365 kb)
Properties of LTP induced in slices from GCN2-/- mice. (PDF 3183 kb)
LTD is normal in GCN2 -/-slices. (PDF 1565 kb)
L-LTP but not E-LTP-inducing protocols regulate GCN2 activity. (PDF 217 kb)
About this article
Cite this article
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
Cell Reports (2020)
The Integrated Stress Response and Phosphorylated Eukaryotic Initiation Factor 2α in Neurodegeneration
Journal of Neuropathology & Experimental Neurology (2020)
The switch-like expression of heme-regulated kinase 1 mediates neuronal proteostasis following proteasome inhibition
Current Opinion in Genetics & Development (2020)
Yeast as a Model to Understand Actin-Mediated Cellular Functions in Mammals—Illustrated with Four Actin Cytoskeleton Proteins