The work to be done in the laboratory of Dr. Guoping Feng at MIT covers the following activities: 1. Provide Shank3 ASD mouse models and assistance for investigating PV neuron dysfunction. In addition to the Shank3 knockout mice we originally shared with Takao Hensch, we have recently developed two new Shank3 models: a conditional Shank3 knockin mouse that allows us to restore Shank3 expression at any developmental stages with Cre-ER, and a conditional Shank3 knockout mouse that allows us to delete Shank3 at any developmental stages with Cre-ER. We will provide these mice for a variety of structural and functional analysis. 2. Develop and provide genetic tools and resources for studying PV neuron function in marmosets. As a Core Facility, we will provide marmoset brain tissues of various developmental stages for studying PV neuron development and function in a primate brain. We will develop GABAergic neuron- specific AAV system for gene manipulations and calcium imaging. Most importantly, we will provide PV neuron-specific knockin marmoset (on-going effort) for viral-mediated, Cre-dependent manipulation of gene function and neuronal imaging in PV neurons. 3. Develop and characterize marmoset models for studying PV neuron dysfunction in ASD. A recent collaborative work between the laboratories of Hensch and Feng using mouse models suggested that PV neuron defects may be a common neuropathology in ASD. Here we propose to further this study by generating and characterizing Shank3 knockout marmosets. These models will allow us to study PV neuron dysfunction in a well-developed primate prefrontal cortex but also dissect cellular and circuitry basis of higher brain function that are disrupted in severe ASD such as eye-gazing, social interaction and cognitive impairment. 4. Provide human stem cells with Shank3 mutations for studying human PV neurons in organoids. In collaboration with Kevin Eggan?s group at Harvard and Lindy Barret at Stanley Center for Psychiatric Research at Broad Institute, we have developed human ES cell lines with Shank3 mutations using CRISPR/Cas9 system. We will provide these cells to Paola Arlotta?s group for developing organoids.
Showing the most recent 10 out of 34 publications
