Joel Richter, in collaboration with Andrei Korostelev, plans to investigate the molecular architecture of FMRP-ribosome interactions at high resolution, to understand how protein synthesis goes awry in fragile X syndrome. This understanding may aid in the development of small molecules that mimic the effects of FMRP on ribosome translocation, which in turn might prove therapeutically useful in the treatment of the disorder.

Heterozygous mutation of CHD8 is strongly associated with autism and results in dysregulated expression of neurodevelopmental and synaptic genes during brain development. In the current project, Albert Basson and Laura Andreae plan to study excitatory and inhibitory synaptic transmission in the prefrontal cortex of Chd8 haploinsufficient mice. Findings from these studies are expected to shed light on how Chd8 mutations disrupt autism-relevant circuits in the developing cortex.

As a supplement to a National Institutes of Health (NIH)-funded IBIS Network study of magnetic resonance imaging predictors of ASD in high familial risk (HR) infants, Shafali Spurling Jeste proposes using electroencephalography and eye-tracking biomarkers to test more scalable predictors of ASD. This study will involve participants from the same cohort as the larger NIH study, which includes recruitment from five sites across the United States. Findings from this project may lead to more accurate early presymptomatic identification and more timely intervention for HR infants.

Kevin Bender and Nadav Ahituv aim to determine whether upregulation of the remaining functional allele with CRISPR activation-based techniques can rescue cellular and behavioral deficits observed in Scn2a heterozygous mice. If successful, this approach may be applicable to other haploinsufficient genes associated with autism spectrum disorders.

To facilitate studies by laboratories with specialized expertise in neural development and brain function, Harold Burgess will create zebrafish lines with individual mutations in five high-confidence ASD risk genes and will provide them to the research community as an unrestricted resource.

Very little is known about the neurobiology of childhood disintegrative disorder (CDD), a rare form of late-onset, severe, regressive autism. Abha Gupta plans to recruit families affected by CDD for clinical characterization and the collection of biospecimens for future neurogenetic analysis.

DEAF1 is an ASD risk gene that is highly expressed in cortical and subcortical regions of the developing human brain. Despite its importance in ASD, the function of DEAF1 in human cortical development is largely unknown. In-Hyun Park plans to investigate the function of DEAF1 using human cortical and thalamic brain organoids.

Shrikanth Narayanan, in collaboration with Somer Bishop, plans to develop ‘transcription-free’ audio analytics based on signal processing and machine-learning techniques that will help support the analysis of speech and language abilities in children with autism.

Previous clinical trials of arbaclofen for the treatment of autism and fragile X syndrome have suffered from large placebo effects and non-optimal outcome measures. Here, Emily Jones and her colleagues propose to incorporate EEG measures into two ongoing arbaclofen clinical trials in order to search for sensitive and predictive biomarkers of treatment efficacy that correlate with behavioral outcomes.

Exploring the consequences of 16p11.2 deletion in diverse species is key to understanding conserved pathophysiological mechanisms that underly the condition in humans. In the current project, Yann Herault plans to develop a new rat model corresponding to the deletion of the 16p11.2 homologous region in the Long-Evans strain. Comparing similarities and differences between rat and mouse models and humans with 16p11.2 deletion syndrome should not only provide a better understanding of the condition, but also has the potential to foster the development of novel therapeutic approaches.