Fragile X syndrome, an autism spectrum disorder and the most common genetic form of intellectual disability in males, is caused by the loss of function of FMRP. In the current project, Gene Yeo plans to investigate whether reduction of a protein antagonist of FMRP can rescue disease-relevant deficits in human stem cell and mouse models of fragile X syndrome.
Autism spectrum disorder (ASD) is a complex condition associated with many different molecular and genetic causes. In the current project, Tim Buschman and colleagues aim to test the hypothesis that these different underlying causes of ASD converge to disrupt the flow of neural activity through the brain. They plan to do this by studying three different mouse models of ASD. Understanding these common disruptions and relating changes in neural activity to behavioral phenotypes will lay the foundation for improving biomarkers and treatments for ASD.
Analyzing when, how, and in which cell types autism spectrum disorder (ASD) pathology arises within the human brain will require a genetically tractable model system that can mimic human embryonic and fetal brain development. In the current project, Jürgen Knoblich’s team plans to combine 3-D tissue culture, CRISPR-based perturbations and single-cell RNA sequencing technology to study transcriptomic alterations in response to loss-of-function mutations in high-risk ASD genes. By characterizing perturbation-induced transcriptomic changes across dozens of cell types in the developing human cortex, they hope to uncover common and unique molecular pathways that bridge genetic mutations to ASD phenotypes.
Chronic gastrointestinal issues, including pain and constipation, are common among individuals with autism spectrum disorder (ASD), yet the mechanisms through which gastrointestinal dysfunction occur in ASD are not understood. The current project aims to investigate the development and function of peripheral sensory neurons that regulate gastrointestinal function in mice and determine whether this neuronal population is dysfunctional in genetic mouse models of ASD.
Sleep disruption may be an important contributor to the core neurodevelopmental, cognitive and social challenges emblematic of autism spectrum disorders (ASDs). As a tool to discover ASD gene networks, Ravi Allada plans to perform high-throughput in vivo behavioral screening assays of transgenic RNA interference libraries in both wild-type fruit flies and flies sensitized with disruptions of ASD risk genes. Specifically, Allada’s team plans to look at altered sleep patterns and circadian rhythms. Future studies of the underlying mechanisms for these genetic pathways may lead to a better understanding of ASD pathophysiology as well as the discovery of novel therapeutic targets.
Discovering the neurophysiological basis of autism is important for understanding its development and testing potential treatments. In the current project, Scott Murray and Sara Jane Webb seek to test a novel neurophysiological hypothesis of disrupted neural inhibition that is specifically related to the removal of excitatory drive. This will involve the use of several neurophysiological recording techniques in human subjects, including electroencephalography and event-related potentials, combined with brain imaging and psychophysical measures of visual sensitivity.
Individuals with autism often report difficulties in processing sensory information. Here, April Levin aims to develop objective measures of how the nervous system processes sensory information, using electroencephalography to measure neural activity in response to sound and touch in both typically developing children and those with autism. The long-term goal of this project is to enhance the understanding of mechanisms underlying sensory processing difficulties in autism, as well as to develop biomarkers for clinical trials.
Neurodevelopmental disorders, at-large, are genetically complex with hundreds of independent risk loci. Disruption of this diverse set of factors ultimately leads to the behaviorally defined clinical phenotypes that we have today, such as autism spectrum disorder (ASD). We still have little understanding of: (1) the core biology (pathophysiology) behind these conditions; (2) whether our clinically defined groups are single conditions or collections of hundreds of similar phenotypic presentations; and (3) how many roads may lead to the same underlying condition.
Gene therapy approaches for the conversion of premature termination codons (PTCs) in SCN2A are currently limited. Christopher Ahern and colleagues have developed a universal approach whereby engineered transfer RNAs (tRNAs) can be used to efficiently correct SCN2A PTCs in vitro and in vivo. The current preclinical study will employ an adeno-associated virus to deliver these tRNA therapeutics to induced pluripotent stem cell (iPSC)-derived cortical cells from individuals who are known to have nonsense mutations in SCN2A to begin to overcome existing technical challenges for a one-time cure for SCN2A channelopathies that involve PTCs.
Sofie Salama and David Haussler will test the hypothesis that changes in NOTCH2NL gene dosage contribute to the neurological phenotypes observed in individuals with autism who carry 1q21.1 distal deletions and duplications. This will be done by re-analyzing existing genome sequencing data from over 4,000 autism families and by developing new long DNA molecule sequencing methods that enable assembly of this complex genomic region in many individuals.