Project Summary/Abstract Communication deficits are the most common disabilities in children, affecting 11% of preschoolers. Although the causes of communication deficits vary, the underlying pathological mechanisms are believed to converge at the level of neural circuitry dysfunction. The focus of this project is to identify deficits in neural function specializations for vocalization processing in a mouse model of Rett Syndrome (MeCP2 loss), a form of autism spectrum disorder (ASD). A core deficiency in ASD is language impairment, which is accompanied by atypical brain lateralization of language processing. This change in a fundamental feature of speech perception disrupts the division of labor between the left and right auditory cortices that is crucial to rapidly parse and decode fleeting vocalizations. The mouse is a relevant species in which to study communication disorders based on the similarities between the murine and human vocalization processing systems. The long-term goal of this laboratory is to develop an efficient pipeline to link ASD risk genes with functional communication deficits, targeting molecular pathways and critical developmental time points for therapeutic intervention. The objective of this proposal is to determine how MeCP2 loss translates into deficits in hemispheric specializations for vocalization processing that are shared between humans and mice. Aim 1 will identify deficits in lateralized function (in vivo), aim 2 will identify abnormalities in the local connectivity of excitatory and inhibitory neuron populations (in vitro), and Aim 3 will examine interhemispheric communication dysfunction. Disruptions in the timing of critical periods are a well-established consequence of MeCP2 loss. Therefore, we predict that this deficit prevents the normal development of lateralized auditory specializations, leading to a loss of the neurotypical hemispheric division of labor that is critical for processing social communication. This approach is innovative because we are the first group to identify lateralized circuit and functional features in auditory cortex, and we can leverage this knowledge to identify abnormalities in hemispheric specializations of vocalization processing. The proposed research is significant because it is expected to reveal fundamental insights into how hemispheric specializations relevant to vocal communication go awry in a mouse model of ASD.