The neuromodulators vasopressin and oxytocin regulate inhibitory tone and sensory processing in the cerebellum. In the current project, Stephanie Rudolph and colleagues aim to manipulate neuromodulatory input in genetic mouse models for autism that have known deficits in cerebellar function with the goal of rescuing behavioral changes.
New technologies for efficiently manipulating genomes have expanded autism research to mammalian models beyond the mouse. Rats are highly social, cooperative animals which, unlike the mouse, live in large social colonies, making them an excellent model species for many of the social characteristics of autism. Peter Kind and colleagues at the Simons Initiative for the Developing Brain plan to generate an in-depth overview of the behavioral repertoire of rats carrying autism-causing genetic alterations. Providing the autism research community with a precise baseline characterization of behavioral phenotypes would help encourage scientific engagement with these models.
Genetic variants contribute significantly to the etiology of autism, and unlike single-nucleotide variants (SNVs), copy number variants (CNVs) are more difficult to detect from genetic sequencing datasets. The goal of this proposal is to significantly increase the yield of high-impact autism mutations by focusing on the discovery of both CNVs and SNVs in autism families from SPARK. Using established and novel computational pipelines, Evan Eichler and colleagues propose to work with the SPARK Consortium to generate a high-confidence set of potential pathogenic variants and then integrate these data into larger genetic variant databases to pinpoint pathogenic variants and novel genes associated with autism.
The transcripts of most high-confidence ASD risk genes bind to the translational regulatory RNA-binding protein CPEB4. In the current project, John Flanagan and colleagues plan to study the function of CPEB4 in mouse cortical development and downstream mRNAs that are regulated by this protein. Findings from these studies are expected to identify principles that link together ASD risk genes and unifying cellular mechanisms that underly ASD pathogenesis.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may induce profound maternal immune activation during pregnancy. Since maternal immune activation has been shown to be associated with adverse neurodevelopmental outcomes in early childhood, it is critical that studies begin to investigate the immunological and neurodevelopmental repercussions to children exposed to SARS-CoV-2 infection in utero. With this goal in mind, Karin Nielsen and collaborators plan to collect maternal-infant specimens over time and to assess neurodevelopmental outcomes in children with antenatal COVID-19 exposure.
Samouil Farhi is a group leader at the Klarman Cell Observatory at the Broad Institute of MIT and Harvard, where he leads the Optical Profiling Platform. He joined the Broad Institute in July 2018 after completing his Ph.D. in chemical biology at Harvard University with Adam Cohen, where he developed methods for all-optical investigations of neuronal systems. The platform’s goal is to bring next-generation imaging approaches to bear on large-scale biological problems, with a focus on profiling the spatial organization of tissues, high-content phenotypic screens and all-optical studies of the electrical properties of cells.
There is a critical unmet need to define ASD-causing genes and determine how variants in those genes perturb molecular networks leading to disease. This project aims to address these issues using robust functional assays in model organisms designed to uncover disease networks and provide clinical predictive values of large numbers of variants. Christopher Loewen and colleagues expect to provide much needed progress in identifying clinically relevant ASD susceptibility variants to improve our understanding of ASD and potential treatments.
Altered sensory processing is a core and predictive feature of ASD but the underlying mechanisms remain poorly understood. By investigating neural information processing during impaired visual perception in Cntnap2 knockout mice, Bilal Haider’s team can begin building a detailed picture of how changes in neural circuits alter perception of the external sensory world.
Although thousands of de novo missense mutations have been detected in people with ASD, it is challenging to identify which mutations induce risk. To address this gap, Haiyuan Yu and Kathryn Roeder aim to continue their efforts to develop an experimentally and computationally integrated interactome perturbation screening pipeline to study these mutations. Additionally, they plan to continue to develop analytical methods to identify ASD risk genes and understand the interrelationships among these genes.
This project plans to compare the process of circuit refinement during developmental critical periods in wild type and monogenic rat models of ASD, to test the hypothesis that experience-dependent circuit refinement during postnatal development is impaired in ASD. Gina Turrigiano and colleagues will use a complex vision-dependent learning task to drive circuit refinement and will relate defects in cellular plasticity mechanisms to altered neural circuit activity and learning.