A ROLE FOR THE RAS SIGNALING PATHWAY IN SYNAPTIC TRANSMISSION AND LONG-TERM-MEMORY

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.