A new study provides evidence for a glia-mediated form of long-term potentiation (LTP) in the rat spinal cord. Activation of astrocytes and microglia induced LTP at spinal C-fibre synapses on lamina I neurons in vitro. Blocking glial metabolism or signalling induced by D-serine, which is released by astrocytes, prevented LTP induction in spinal C-fibres after high-frequency stimulation (HFS) of the sciatic nerve. Finally, spinal superfusate from mice that underwent such HFS induced LTP in C-fibres in naive animals, and this was blocked by inhibiting signalling by D-serine or tumour necrosis factor, also released by glia.