Regulation of long-term potentiation by H-Ras through NMDA receptor phosphorylation

The proto-oncogene ras plays a critical role in cell proliferation and diff erentiation. However, ras genes are abundantly expressed in the adult CNS, although neuronal cells normally do not proliferate. Recently, several line s of evidence implicated the involvement of Ras signaling pathway in synapt ic plasticity. To explore the role of the Ras proteins in the CNS, we gener ated knock-out mice lacking the H-ras gene and then used them to study the roles of Ras in synaptic transmission and plasticity. An investigation of p rotein phosphorylation and synaptic transmission in H-ras null mutant mice has shown that the NMDA receptor is a final target molecule of the Ras prot ein pathway in the CNS. In the H-ras null mutant hippocampus, the tyrosine phosphorylation of NR2A (epsilon 1) and NR2B (epsilon 2) subunits of NMDA r eceptors is increased, and, correspondingly, NMDA synaptic responses are se lectively enhanced. In addition, long-term potentiation is markedly enhance d in mutant mice, most likely because of a selective enhancement of NMDA sy naptic responses. Therefore, although Ras proteins have been implicated in cell proliferation and differentiation, the regulation of activity-dependen t synaptic plasticity in the adult animals by downregulation of the phospho rylation of the NMDA receptor may be another major and pivotal role for H-R as protein.