In neurons, individual dendritic spines isolate N -methyl- d -aspartate (NMDA) receptor–mediated calcium ion (Ca ²⁺ ) accumulations from the dendrite and other spines. However, the extent to which spines compartmentalize signaling events downstream of Ca ²⁺ influx is not known. We combined two-photon fluorescence lifetime imaging with two-photon glutamate uncaging to image the activity of the small guanosine triphosphatase Ras after NMDA receptor activation at individual spines. Induction of long-term potentiation (LTP) triggered robust Ca ²⁺ -dependent Ras activation in single spines that decayed in ∼5 minutes. Ras activity spread over ∼10 micrometers of dendrite and invaded neighboring spines by diffusion. The spread of Ras-dependent signaling was necessary for the local regulation of the threshold for LTP induction. Thus, Ca ²⁺ -dependent synaptic signals can spread to couple multiple synapses on short stretches of dendrite.