title: Translational control of hippocampal synaptic plasticity and memory by the eIF2alpha 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 proteins. 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.
authors.affiliation: Department of Biochemistry and McGill Cancer Center, Montreal, Quebec, Canada
authors.forename: Mauro
authors.initials: M
authors.lastname: Costa-Mattioli
authors.forename: Delphine
authors.initials: D
authors.lastname: Gobert
authors.forename: Heather
authors.initials: H
authors.lastname: Harding
authors.forename: Barbara
authors.initials: B
authors.lastname: Herdy
authors.forename: Mounia
authors.initials: M
authors.lastname: Azzi
authors.forename: Martin
authors.initials: M
authors.lastname: Bruno
authors.forename: Michael
authors.initials: M
authors.lastname: Bidinosti
authors.forename: Cyrinne
authors.initials: C
authors.lastname: Ben Mamou
authors.forename: Edwige
authors.initials: E
authors.lastname: Marcinkiewicz
authors.forename: Madoka
authors.initials: M
authors.lastname: Yoshida
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Imataka
authors.forename: A Claudio
authors.initials: AC
authors.lastname: Cuello
authors.forename: Nabil
authors.initials: N
authors.lastname: Seidah
authors.forename: Wayne
authors.initials: W
authors.lastname: Sossin
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Lacaille
authors.forename: David
authors.initials: D
authors.lastname: Ron
authors.forename: Karim
authors.initials: K
authors.lastname: Nader
authors.forename: Nahum
authors.initials: N
authors.lastname: Sonenberg
mesh_terms: D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D003214:Conditioning, Classical / Q000502:physiology; D005239:Fear / Q000502:physiology; D017353:Gene Deletion; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D018782:Maze Learning / Q000502:physiology; D008568:Memory / Q000502:physiology*; D051379:Mice; D009473:Neuronal Plasticity / Q000235:genetics / Q000502:physiology*; D014176:Protein Biosynthesis; D011494:Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013569:Synapses / Q000201:enzymology / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D005576:Colforsin; D011494:Protein Kinases; C070634:Eif2ak4 protein, mouse; D017346:Protein Serine-Threonine Kinases