Members of the Ras subfamily of small guanine-nucleotide-binding prote
ins are essential for controlling normal and malignant cell proliferat
ion as well as cell differentiation(1). The neuronal-specific guanine-
nucleotide-exchange factor, Ras-GRF/CDC25Mm (refs 2-4), induces Ras si
gnalling in response to Ca2+ influx(5) and activation of G-protein-cou
pled receptors in vitro(6), suggesting that it plays a role in neurotr
ansmission and plasticity in vivo(7). Here we report that mice lacking
Ras-GRF are impaired in the process of memory consolidation, as revea
led by emotional conditioning tasks that require the function of the a
mygdala; learning and short-term memory are intact. Electrophysiologic
al measurements in the basolateral amygdala reveal that long-term plas
ticity is abnormal in mutant mice. In contrast, Ras-GRF mutants do not
reveal major deficits in spatial learning tasks such as the Morris wa
ter maze, a test that requires hippocampal function. Consistent with a
pparently normal hippocampal functions, Ras-GRF mutants show normal NM
DA (N-methyl-D-aspartate) receptor-dependent long-term potentiation in
this structure. These results implicate Ras-GRF signalling via the Ra
s/MAP kinase pathway in synaptic events leading to formation of long-t
erm memories.