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 1 . The neuronal-specific guanine-nucleotide-exchange factor, Ras-GRF/CDC25Mm ( refs 2 , 3 , 4 ), induces Ras signalling in response to Ca 2+ influx 5 and activation of G-protein-coupled receptors in vitro 6 , suggesting that it plays a role in neurotransmission and plasticity in vivo 7 . 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.