Selective Deletion of Methyl CpG Binding Protein 2 from Parvalbumin Interneurons in the Auditory Cortex Delays the Onset of Maternal Retrieval in Mice

Abstract

Mutations inMECP2cause the neurodevelopmental disorder Rett syndrome.MECP2codes for methyl CpG binding protein 2 (MECP2), a transcriptional regulator that activates genetic programs for experience-dependent plasticity. Many neural and behavioral symptoms of Rett syndrome may result from dysregulated timing and thresholds for plasticity. As a model of adult plasticity, we examine changes to auditory cortex inhibitory circuits in female mice when they are first exposed to pups; this plasticity facilitates behavioral responses to pups emitting distress calls. Brainwide deletion ofMecp2alters expression of markers associated with GABAergic parvalbumin interneurons (PVins) and impairs the emergence of pup retrieval. We hypothesized that loss ofMecp2in PVins disproportionately contributes to the phenotype. Here, we find that deletion ofMecp2from PVins delayed the onset of maternal retrieval behavior and recapitulated the major molecular and neurophysiological features of brainwide deletion ofMecp2. We observed that when PVin-selective mutants were exposed to pups, auditory cortical expression of PVin markers increased relative to that in wild-type littermates. PVin-specific mutants also failed to show the inhibitory auditory cortex plasticity seen in wild-type mice on exposure to pups and their vocalizations. Finally, using an intersectional viral genetic strategy, we demonstrate that postdevelopmental loss ofMecp2in PVins of the auditory cortex is sufficient to delay onset of maternal retrieval. Our results support a model in which PVins play a central role in adult cortical plasticity and may be particularly impaired by loss ofMecp2.SIGNIFICANCE STATEMENTRett syndrome is a neurodevelopmental disorder that includes deficits in both communication and the ability to update brain connections and activity during learning (plasticity). This condition is caused by mutations in the geneMECP2. We use a maternal behavioral test in mice requiring both vocal perception and neural plasticity to probe the role ofMecp2in social and sensory learning.Mecp2is normally active in all brain cells, but here we remove it from a specific population (parvalbumin neurons). We find that this is sufficient to delay learned behavioral responses to pups and recreates many deficits seen in whole-brainMecp2deletion. Our findings suggest that parvalbumin neurons specifically are central to the consequences of loss ofMecp2activity and yield clues as to possible mechanisms by which Rett syndrome impairs brain function.