The late phase of long-term potentiation (LTP) at glutamatergic synapses, which is thought to underlie long-lasting memory, requires gene transcription in the nucleus. However, the mechanism by which signaling initiated at synapses is transmitted into the nucleus to induce transcription has remained elusive. Here, we found that induction of LTP in only three to seven dendritic spines in rat CA1 pyramidal neurons was sufficient to activate extracellular signal-regulated kinase (ERK) in the nucleus and regulate downstream transcription factors. Signaling from individual spines was integrated over a wide range of time (>30 minutes) and space (>80 micrometers). Spatially dispersed inputs over multiple branches activated nuclear ERK much more efficiently than clustered inputs over one branch. Thus, biochemical signals from individual dendritic spines exert profound effects on nuclear signaling.