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.

About 15 percent of individuals with autism have an identifiable gene-disrupting mutation that contributes strongly to their symptoms. Some of these gene-disrupting mutations act by changing how the mRNA is spliced prior to making a protein. In this project, Stephan Sanders aims to apply recent advances in the detection of these splicing mutations to autism sequencing data, validate the splicing disruption independently and assess whether antisense oligonucleotides can restore typical gene function.

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.

Gastrointestinal issues are a comorbidity of ASD and individuals with mutations in CHD8 often display such symptoms. In the current project, Evan Elliott and colleagues plan to study Chd8 heterozygous mice to explore the role of Chd8 on gut epithelial cell function. Findings from this study are expected to lead to a better understanding of the relationship between Chd8 haploinsufficiency, gastrointestinal issues and behavioral phenotypes relevant to ASD.