Sociability is crucial for survival, whereas social avoidance is a feature of disorders such as Rett syndrome, which is caused by loss-of-function mutations in MECP2. To understand how a preference for social interactions is encoded, we used in vivo calcium imaging to compare medial prefrontal cortex (mPFC) activity in female wild-type and Mecp2-heterozygous mice during three-chamber tests. We found that mPFC pyramidal neurons in Mecp2-deficient mice are hypo-responsive to both social and nonsocial stimuli. Hypothesizing that this limited dynamic range restricts the circuit’s ability to disambiguate coactivity patterns for different stimuli, we suppressed the mPFC in wild-type mice and found that this eliminated both pattern decorrelation and social preference. Conversely, stimulating the mPFC in MeCP2-deficient mice restored social preference, but only if it was sufficient to restore pattern decorrelation. A loss of social preference could thus indicate impaired pattern decorrelation rather than true social avoidance.

Even symptomatic Mecp2 -null mice can develop motor skills, which improve behavior and extend life span by 20%.

Motor cortex displays remarkable plasticity during motor learning. However, it remains largely unknown how the highly dynamic motor cortical circuit reorganizes during reward-independent procedural learning at the populational level. Machine learning-based analysis of the neuronal events recorded with in vivo two-photon calcium imaging revealed procedural learning-induced 5 circuit reorganization in superficial but not deep layers of the motor cortex while mice learned to run on a speed-controlled treadmill. Mice lacking Methyl-CpG-binding protein (MeCP2), an animal model for Rett Syndrome, exhibited impaired both procedural learning and dynamic circuit reorganization in layer 2/3, but not layer 5a. These results identify potential circuit mechanisms underlying motor skill learning disability caused by MeCP2 deletion and provide insight in 10