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

Mauro Costa-Mattioli, Delphine Gobert, Heather Harding, Barbara Herdy, Mounia Azzi, Martin Bruno, Michael Bidinosti, Cyrinne Ben Mamou, Edwige Marcinkiewicz, Madoka Yoshida, Hiroaki Imataka, A. Claudio Cuello, Nabil Seidah, Wayne Sossin, Jean-Claude Lacaille, David Ron, Karim Nader and Nahum Sonenberg ()
Additional contact information
Mauro Costa-Mattioli: Department of Biochemistry and McGill Cancer Center
Delphine Gobert: Université de Montréal
Heather Harding: NYU School of Medicine
Barbara Herdy: Department of Biochemistry and McGill Cancer Center
Mounia Azzi: Université de Montréal
Martin Bruno: Department of Pharmacology and Therapeutics
Michael Bidinosti: Department of Biochemistry and McGill Cancer Center
Cyrinne Ben Mamou: Department of Psychology
Edwige Marcinkiewicz: Clinical Research Institute of Montreal
Madoka Yoshida: Department of Biochemistry and McGill Cancer Center
Hiroaki Imataka: RIKEN
A. Claudio Cuello: Department of Pharmacology and Therapeutics
Nabil Seidah: Clinical Research Institute of Montreal
Wayne Sossin: McGill University
Jean-Claude Lacaille: Université de Montréal
David Ron: NYU School of Medicine
Karim Nader: Department of Psychology
Nahum Sonenberg: Department of Biochemistry and McGill Cancer Center

Nature, 2005, vol. 436, issue 7054, 1166-1170

Abstract: 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.

Date: 2005
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DOI: 10.1038/nature03897

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