DNA methylation is a key epigenetic modification that is disrupted in a subset of ASD cases. In the current project, Hume Stroud aims to assess regulatory mechanisms affecting the activity of the DNA cystine methyltransferase DNMT3A and whether there is a critical window during which DNMT3A function can be restored in mouse models.
Computational gene risk prediction methods and network-based analyses are major tools in analyzing large-scale autism genomic studies for (i) imputing the insufficient statistical signal and providing a genome-wide risk ranking and (ii) finding out the affected cellular circuitries such as pathways and networks of genes. Here, Ercüment Çiçek and his team plan to develop a novel cross-disorder gene discovery algorithm that can analyze related disorders simultaneously and explicitly learn shared and disorder-specific genetic components.
ASD is believed to modify the balance of excitation and inhibition in brain circuits and is frequently accompanied by seizures, but precisely how and why this occurs is poorly understood. In this project, Sacha Nelson and colleagues plan to use an in vitro slice culture platform in combination with calcium imaging techniques to record activity from brain regions important for sensation and memory in four established genetic mouse models of ASD. By studying changes in neuronal and epileptiform activity over development, the progression of brain pathology and the mechanisms that normally compensate for it will be better understood.
Using new magnetic resonance imaging techniques and analysis approaches to identify focal cortical dysplasias (FCDs), Ruth Carper aims to determine whether FCDs occur more frequently in individuals with ASDs than is currently appreciated and to understand what effects FCDs have on cognition and behavior in ASD.
Frank McCormick will address the biochemical mechanism by which mutations in SYNGAP1 drive ASD and intellectual disability. Elucidation of the mechanism of SYNGAP1 negative regulation of RAS and its effector pathways in neurons will further our understanding of the role of this pathway in health and disease, and will shed light on potential ways in which targeted RAS pathway inhibition may be therapeutically relevant.
J. Elliott Robinson plans to create gene therapies to address cognitive symptoms in neurofibromatosis type 1 (NF1) using a combination of protein engineering methods, CRISPR activation-based approaches to regulate endogenous gene expression and new systemic AAV capsids that freely cross the blood-brain barrier after intravenous administration. The resulting vectors will be tested in NF1 model mice in vivo and disseminated to the larger research community for additional validation.
Denis Sukhodolsky and Kevin Pelphrey will perform a randomized clinical trial of oxytocin to determine if it can enhance responses to Pivotal Response Training in young children with autism. Functional magnetic resonance brain imaging and eye tracking measures will be studied in conjunction with key behavioral outcomes. This study will aid in the development of more precise treatments for children with ASD that are guided by objective neurobiological markers.
Gabriela Rosenblau aims to describe how children with ASD learn about others, how learning strategies are implemented in the brain and how learning strategies predict children’s individual treatment outcomes. By providing precise, computational model-based analyses, this project will help guide more targeted behavioral treatments across the autism spectrum.
Sensory hypersensitivity is a central issue in autism and autism-related disorders like fragile X syndrome but relatively little is known about the underlying brain mechanisms. In this project, Richard Salvi plans to combine the use of novel behavioral assays for assessing sound hypersensitivity in rats with state-of-the-art electrophysiological and analytical techniques to determine the nature of auditory perceptual and circuit abnormalities in a rat model of fragile X syndrome.
Although autism is highly heritable, its heterogeneity has challenged gene-finding efforts. Daniel Geschwind and his colleagues at the University of California, Los Angeles, propose to identify the gene networks frequently dysregulated in people with autism, regardless of the underlying mutations.