A role for the Ras signalling pathway in synaptic transmission and long-term memory.
Members of the Ras subfamily of small guanine-nucleotide-binding proteins are essential for controlling normal and malignant cell proliferation as well as cell differentiation. The neuronal-specific guanine-nucleotide-exchange factor, Ras-GRF/CDC25Mm, induces Ras signalling in response to Ca2+ influx and activation of G-protein-coupled receptors in vitro, suggesting that it plays a role in neurotransmission and plasticity in vivo. Here we report that mice lacking Ras-GRF are impaired in the process of memory consolidation, as revealed by emotional conditioning tasks that require the function of the amygdala; learning and short-term memory are intact. Electrophysiological measurements in the basolateral amygdala reveal that long-term plasticity is abnormal in mutant mice. In contrast, Ras-GRF mutants do not reveal major deficits in spatial learning tasks such as the Morris water maze, a test that requires hippocampal function. Consistent with apparently normal hippocampal functions, Ras-GRF mutants show normal NMDA (N-methyl-D-aspartate) receptor-dependent long-term potentiation in this structure. These results implicate Ras-GRF signalling via the Ras/MAP kinase pathway in synaptic events leading to formation of long-term memories.
Brambilla
R
R
European Molecular Biology Laboratory, Heidelberg, Germany.
Gnesutta
N
N
Minichiello
L
L
White
G
G
Roylance
A J
AJ
Herron
C E
CE
Ramsey
M
M
Wolfer
D P
DP
Cestari
V
V
Rossi-Arnaud
C
C
Grant
S G
SG
Chapman
P F
PF
Lipp
H P
HP
Sturani
E
E
Klein
R
R
D016475:3T3 Cells; D000679:Amygdala / Q000502:physiology; D000818:Animals; D001362:Avoidance Learning; D001921:Brain / Q000473:pathology / Q000502:physiology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology*; D003214:Conditioning, Classical; D004594:Electrophysiology; D005239:Fear; D006624:Hippocampus / Q000502:physiology; D018782:Maze Learning; D008568:Memory / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016296:Mutagenesis; D009473:Neuronal Plasticity; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D013037:Spatial Behavior; D013569:Synapses / Q000502:physiology*; D018631:ras Proteins / Q000502:physiology*; D020666:ras-GRF1
D018797:Cell Cycle Proteins; D020666:ras-GRF1; D010749:Phosphoprotein Phosphatases; D018631:ras Proteins