On-demand expression of a gene that inhibits neuronal activity provides a way to reduce spontaneous seizures in mice, researchers report. In a new study, Yichen Qiu and colleagues present a closed-loop gene therapy approach to treat brain circuit disorders where only a subpopulation of neurons is problematically overactive, including epilepsy. Spontaneous and intermittent seizures characterize neurodevelopmental and neuropsychiatric disorders like epilepsy. Although these episodes can be reduced through antiseizure medication, nearly one-third of epilepsy patients fail to respond to these treatments. Others that initially respond favorably can subsequently develop tolerance. Outside of pharmacological solutions, several gene therapy strategies have shown promise. However, these methods tend to indiscriminately target all neurons in a given brain region rather than the specific problematic circuits responsible for triggering the episode. To address this, Qui et al. developed a gene therapy strategy that self-selects pathologically overreactive neurons and down regulates their excitability in a closed-loop feedback system. The approach uses the Fos gene, whose expression is up-regulated by neuronal activity, including seizures, to control the Kcna1 gene, which encodes an inhibitory gene that quiets neuronal activity. Qiu et al. used an adeno-associated virus vector encoding the Fos promoter and Kcna1 to transfect neurons in a mouse model of epilepsy. During periods of intense neuronal activity, Fos promoted the expression of Kcna1, but only in hyperactive neurons and only for as long as they exhibited abnormal activity. According to the findings, neuronal excitability was reduced in these cells by the seizure-related activity, thus, offering a persistent antiepileptic effect that did not interfere with normal behaviors. In a related Perspective, Kevin Staley discusses the new approach in greater detail.