Keerthi Krishnan, Billy Lau, Gabrielle Ewall, Z. Josh Huang, Stephen David Shea
Neurodevelopmental disorders begin with the emergence of inappropriate synaptic connectivity early in life, yet how the sustained disruption of experience-dependent plasticity aggravates symptoms in adulthood is unclear. Here we used pup retrieval learning to assay adult cortical plasticity in a female mouse model of Rett syndrome (MeCP2het). We show that auditory cortical plasticity and retrieval learning are impaired in MeCP2het. Specifically, normal MECP2 expression in the adult auditory cortex is required for efficient retrieval learning. In wild-type mice, cohabitation with a mother and her pups triggered transient changes to auditory cortical inhibitory networks, including elevated levels of the GABA-synthesizing enzyme GAD67. However, MeCP2het further exhibited increased expression of parvalbumin (PV) and perineuronal nets (PNNs), events thought to suppress plasticity at the closure of critical periods and in adult learning. Averting these events with genetic and pharmacological manipulations of the GABAergic network restored retrieval behavior. We propose that adult retrieval learning triggers a transient episode of inhibitory plasticity in the auditory cortex that is dysregulated in MeCP2het. This window of heightened sensitivity to social sensory cues reveals a role of MeCP2 mutations in facilitating adult plasticity that is distinct from their effects on early development.