A novel neural circuit analysis paradigm to model autism in mice

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A Novel Neural Circuit Analysis Paradigm to Model Autism in Mice The circuit defects underlying the behavioral impairments of autism spectrum disorders (ASD) remains poorly understood. This knowledge is critical for development of effective treatments. The considerable molecular heterogeneity in human ASD and the apparent limitations in human studies renders mutant mice with targeted mutations equivalent to humans a unique opportunity because it allows manipulation at both molecular and circuit levels. There is an increasing list of ASD models with both "construct" (molecular defect mimics human ASD) and "face" (behavioral impairments equivalent to core feature of human ASD) validity. The current analytic paradigm of modeling human ASD in mutant mice focuses on analyzing synaptic development and function using slice physiology and behavior analysis. These studies have produced evidence supporting a general conclusion of synaptic dysfunction in ASD models. However, these findings offer little insight into the circuit mechanism underlying behavioral impairments because the findings from studying the synapses in select brain regions are frequently variable and inconsistent among different studies. The fundamental challenge of ASD research lies within the complexity of understanding how alterations in gene function disrupt large scale brain networks responsible for normal functional process underlying autistic behaviors. For these reasons, the field of modeling human ASD in genetically modified mutant mice demands a new analytic paradigm to dissect the dysfunction at circuit or network levels. We have developed a novel multi-unit in vivo recoding technique that can acquire neural activity from as many as 11 brain regions in free moving animals simultaneously. This novel technique offers a feasibility to detect dysfunctional neural circuit and network. We have also produced and characterized unique Shank2 exon 24 (Shank3e24) and Shank3 exon 4-22 (Shank3e4- 22) deletion mutant mice that have strong construct and face validity for human ASD. These mutant mice provide unique opportunities to develop a novel analytic paradigm for dissecting circuit dysfunction. The long term goal of this project is to define dysfunctional circuit underlying ASD behaviors using ASD mouse models. The central hypothesis is dysfunction synchrony across distinct relevant neural circuits will be observed in Shank3e4-22 and Shank2e24 mutant mice. The specific objective is to identify the dysfunctional neural circuits underlying social deficits and repetitive behaviors in these mutant mice using a novel in vivo multiple-unit recording technique pioneered by our team. These experiments will lead to the identification of electrophysiological biomarkers of endophenotypes that will aid in the validation of novel molecular targets for novel neuropsychiatric drugs, enhance the targeting of current neuromodulatory therapies for use in ASD and facilitate the development of closed loop neuromodulatory "pacemakers" which directly repair the dysfunctional brain circuits underlying the behavioral manifestations in ASD. These findings will address a significant gap in our knowledge and provide evidence to support a paradigm shift in modeling human ASD using mutant mice.