Knockout of ERK1 MAP kinase enhances synaptic plasticity in the striatum and facilitates striatal-mediated learning and memory.
Extracellular signal-regulated kinases (ERK1 and 2) are synaptic signaling components necessary for several forms of learning. In mice lacking ERK1, we observe a dramatic enhancement of striatum-dependent long-term memory, which correlates with a facilitation of long-term potentiation in the nucleus accumbens. At the cellular level, we find that ablation of ERK1 results in a stimulus-dependent increase of ERK2 signaling, likely due to its enhanced interaction with the upstream kinase MEK. Consistently, such activity change is responsible for the hypersensitivity of ERK1 mutant mice to the rewarding properties of morphine. Our results reveal an unexpected complexity of ERK-dependent signaling in the brain and a critical regulatory role for ERK1 in the long-term adaptive changes underlying striatum-dependent behavioral plasticity and drug addiction.
Mazzucchelli
Cristina
C
San Raffaele Research Institute and University, via Olgettina 58, 20132 Milano, Italy.
Vantaggiato
Chiara
C
Ciamei
Alessandro
A
Fasano
Stefania
S
Pakhotin
Pavel
P
Krezel
Wojciech
W
Welzl
Hans
H
Wolfer
David P
DP
Pagès
Gilles
G
Valverde
Olga
O
Marowsky
Anne
A
Porrazzo
Annamaria
A
Orban
Paul C
PC
Maldonado
Rafael
R
Ehrengruber
Markus U
MU
Cestari
Vincenzo
V
Lipp
Hans-Peter
HP
Chapman
Paul F
PF
Pouysségur
Jacques
J
Brambilla
Riccardo
R
D000679:Amygdala / Q000166:cytology / Q000201:enzymology; D000818:Animals; D001362:Avoidance Learning / Q000502:physiology; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D003072:Cognition Disorders / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D003342:Corpus Striatum / Q000002:abnormalities / Q000166:cytology / Q000201:enzymology*; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000201:enzymology; D017774:Long-Term Potentiation / Q000235:genetics*; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D008297:Male; D008568:Memory / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000172:deficiency* / Q000235:genetics; D009020:Morphine / Q000494:pharmacology; D009043:Motor Activity / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009415:Nerve Net / Q000002:abnormalities / Q000166:cytology / Q000201:enzymology; D009421:Nervous System Malformations / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D009714:Nucleus Accumbens / Q000002:abnormalities / Q000166:cytology / Q000201:enzymology*; D017729:Presynaptic Terminals / Q000201:enzymology* / Q000648:ultrastructure; D009435:Synaptic Transmission / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics
D009020:Morphine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases