Development of Corticothalamic Circuits of Prefrontal Cortex in ASD

Autism spectrum disorders (ASD) represent a group of developmental neuropsychiatric disorders for which the underlying etiologies are heterogeneous. Risk factors range from environmental insults to single gene mutations, yet all result in abnormalities in communication, social interactions, and repetitive behavior. How these heterogeneous etiologies lead to defects in language, cognition and multiple sensory and motor modalities remains unclear. Here we propose the hypothesis that disrupted development of circuits between prefrontal cortex and thalamus contribute to many of the core symptoms in ASD. Specifically, we focus on circuits between prefrontal cortex and the thalamic reticular nucleus (TRN), a thalamic nucleus that integrates information from multiple sensory, motor and limbic cortical regions. Corticothalamic projections from prefrontal cortex, a region important for social behavior, is known to mature late in development, and disruptions of cortical activity during this period may lead to disrupted social and sensory integration. Little is know of how this circuit develops, or whether this circuit is abnormal in mouse models of ASD. Therefore, in this pilot grant we will characterize the development of the circuit between prefrontal cortex and TRN as well as that between different modality sectors of TRN in two monogenetic models of ASD, Shank 3 and FMR1. We will also perturb this corticothalamic circuit in normally developing mice to examine changes in the plasticity of this circuit. Our hypothesis predicts that focal defects in the prefrontal cortex of these ASD mouse models can lead to progressively abnormal development of subcortical networks important in gating social, sensory and motor information. If our hypothesis is validated by these experiments, this model may provide a unifying framework for approaching neurodevelopmental disorders such as ASD.