Genetic dissection of cortical projection neurons in social brain circuits

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The autism spectrum disorders (ASDs) are characterized by impairments of social and communicative behavior. The different, yet specific behavioral phenotypes of autism suggest impairments of specific neural circuits of the social brain. Yet, as genetic studies of autism implicate several hundred gene variants, it remains unclear how these genetic variants cause the behavioral phenotypes of autism. Several studies have implicated dysregulation of gene expression in the cerebral cortex in the pathophysiology of ASD. However, they do not address the specificity of cell types involved, how genetic changes alter brain function, or the involvement of functionally specific brain areas. Thus, we do not know whether and how they are altering social brain function selectively or what it is about social brain function that makes it particularly vulnerable in autism. In order to understand autism and its causes, we need to understand how genetic alterations cause the specific changes in the brain circuits that mediate the social and communicative behaviors altered in the condition. The current proposal aims to establish a new approach and a new model system to answer these questions. Using an animal model close to humans, gene expression patterns in functionally defined circuits of the social brain will be characterized. As in human functional magnetic resonance imaging (fMRI) studies, functionally specific regions of the social brain will be localized. This pilot proposal will focus on face-selective brain regions, but the overall approach, once established, will easily translate to other systems. The functional characterizations of the social brain will be complemented by the determination of the connectome of face areas through diffusion-weighted brain imaging. With this knowledge, long-range projection neurons within this functionally defined network will be labeled through a retrograde adeno-associated virus and cell-type specific gene expression patterns will be measured using the Translating Ribosome Affinity Purification (TRAP). The approach will allow for the determination of these expression patterns in glutamatergic cortical projection neurons located in the supra- and infra-granular cortical layers. These are the exact neurons which two recent studies have found to be highly correlated with ASD risk genes. Gene expression patterns of projection neurons will be compared in functionally defined social brain areas to known catalogs of autism-associated gene variations and pathways. The main expected outcome of this study will be the first determination of autism-risk gene expression patterns of functionally identified nodes of the social brain. The rationale of this study is that it will allow us to link autism risk genes to social brain circuits, advance the development of etiological models of autism, and provide crucial information for the generation of transgenic non-human primate autism models. In doing so, critical new links will be forged between the genetic analysis of ASD and functional imaging of brain function in ASD.