Sensory experience alters cortical circuitry by parallel processes of axon outgrowth and pruning, but the mechanisms that control these rearrangements are poorly understood. Usingin vivo2-photon longitudinal imaging, we found a marked reduction in axonal pruning in somatosensory cortex of mice with a knock-out of theDR6gene, which codes for Death Receptor 6. This effect was seen for both long-range horizontal excitatory connections and for the axons of inhibitory neurons. These results identify a new pathway governing axonal plasticity associated with experience-dependent changes in cortical maps.