Translational control of hippocampal synaptic plasticity and memory by the eIF2alpha kinase GCN2.
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.
Costa-Mattioli
Mauro
M
Department of Biochemistry and McGill Cancer Center, Montreal, Quebec, Canada
Gobert
Delphine
D
Harding
Heather
H
Herdy
Barbara
B
Azzi
Mounia
M
Bruno
Martin
M
Bidinosti
Michael
M
Ben Mamou
Cyrinne
C
Marcinkiewicz
Edwige
E
Yoshida
Madoka
M
Imataka
Hiroaki
H
Cuello
A Claudio
AC
Seidah
Nabil
N
Sossin
Wayne
W
Lacaille
Jean-Claude
JC
Ron
David
D
Nader
Karim
K
Sonenberg
Nahum
N
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*
D012333:RNA, Messenger; D005576:Colforsin; D011494:Protein Kinases; C070634:Eif2ak4 protein, mouse; D017346:Protein Serine-Threonine Kinases