The numerous changes in synaptic physiology and structure that occur in epilepsy are not effectively targeted by the currently available anti-epileptic therapies. Here, Jimenez-Mateos et al. found that miR-134 — a brain-specific microRNA reported to be involved in regulating spine morphology — was upregulated in the brain of patients with epilepsy and in a mouse model of epilepsy. Pharmacological silencing of miR-134 in mice through the use of antagomirs attenuated seizure severity during status epilepticus and reduced cell death and classical hallmarks of epilepsy, such as astrogliosis.