Abstract
Social behavior depends on neural circuits that encode social identity, memory, and motivational value. These processes engage coordinated activity across hippocampal subregions, medial prefrontal cortex, thalamic and hypothalamic nuclei, as well as the mesocorticolimbic dopaminergic systems that regulate internal state, hierarchy, and social reward. In Rett syndrome and MeCP2-deficient rodent models, basic sociability is often preserved, alongside impairments in social memory, dominance behavior, aggression control, and flexible social responding, frequently accompanied by anxiety-like and sensorimotor disturbances. These behavioral phenotypes are associated with MeCP2-dependent molecular dysfunctions, including altered activity-dependent transcription, reduced BDNF-TrkB signaling, disrupted synaptic maturation, and altered network activity within prefrontal and hippocampal circuits. Together, these findings indicate that Rett-related social deficits reflect impaired integration and valuation of social information rather than a primary loss of social interest. Understanding how MeCP2 regulates the development and function of distributed social circuits may inform strategies to restore adaptive social behavior in Rett syndrome and related neurodevelopmental disorders.