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Neurodevelopmental disorders are marked by inappropriate synaptic connectivity early in life, but how disruption of experience-dependent plasticity contributes to cognitive and behavioural decline in adulthood is unclear. Here we show that pup gathering behaviour and associated auditory cortical plasticity are impaired in female  Mecp2   het   mice, a model of Rett syndrome. In response to learned maternal experience,  Mecp2   het   females exhibited transient changes to cortical inhibitory networks typically associated with limited plasticity. Averting these changes in  Mecp2   het   through genetic or pharmacological manipulations targeting the GABAergic network restored gathering behaviour. We propose that pup gathering learning triggers a transient epoch of inhibitory plasticity in auditory cortex that is dysregulated in  Mecp2   het  . In this window of heightened sensitivity to sensory and social cues,  Mecp2  mutations suppress adult plasticity independently from their effects on early development.

MECP2 regulates cortical plasticity underlying a learned behaviour in adult female mice