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.

In this project, Bence Ölveczky aims to garner insight into the neural circuit-level changes associated with autism and how these lead to motor-related manifestations of the condition. To this end, the project will combine long-term continuous neural recordings in the striatum with quantitative measurements of behavior in freely behaving rats.

The syndromic autism gene, MEF2C, plays an essential role in both neuronal and neuroimmune aspects of brain development and function. In the current project, Christopher Cowan, Hainan Lang and Bärbel Rohrer aim to explore the impact of neuroimmune Mef2c hypofunction on the development and function of mouse auditory and visual sensory systems.

Nael Nadif Kasri will assess differences in neuronal network activity and transcriptional profiles in neural cells derived from induced pluripotent stem cells from individuals with syndromic forms of ASD, building a phenotypic map based on network activity and cellular profiles. These phenotypic maps will aid in the dissection of the underlying cellular and molecular mechanisms involved in distinct forms of ASD.

Each individual with ASD is unique, and understanding this variability is essential for both biomarker and treatment development. Joshua Hartshorne and Stefano Anzellotti plan to use Bayesian nonparametric techniques to analyze functional brain imaging data from individuals with ASD and related neurodevelopmental disorders. The goal of the study is to identify an optimal model that captures variability and clusters the data based on either subtypes of ASD or a set of dimensions; such a subclassification system will be useful for tailoring individual-specific interventions.

Dysregulated protein synthesis underlies several brain disorders, including ASD. In this project, Arkady Khoutorsky will use a mouse model of fragile X syndrome (Fmr1 knockout mice) to examine cell-type-specific alterations in the integrated stress response (ISR) pathway — a pathway that is central to the regulation of protein synthesis in the brain. He will assess the hypothesis that dysregulation of ISR pathway-dependent protein synthesis leads to an altered repertoire of proteins that subsequently contributes to aberrant activity of neuronal circuits and behavioral phenotypes in Fmr1 knockout mice.

Disrupted cerebrospinal fluid (CSF) volume and composition, as well as ventricle formation, are common to many neurodevelopmental disorders, including ASD. Alterations in serotonergic signaling have also been implicated in ASD, yet the sensitivity of the choroid plexus (the primary source of CSF) to serotonin has not been well studied. Maria Lehtinen plans to directly test the consequences of manipulating serotonergic signaling at the choroid plexus. Her team will assess how alterations in serotonergic signaling affect the choroid plexus secretome and cortical development in 16p11.2 deletion mice.