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.

The neuron-specific potassium-chloride co-transporter, KCC2, is involved in the regulation of excitatory and inhibitory neuronal activity. It has been identified as a promising therapeutic target for autism. In the current project, Charles Craik’s laboratory and collaborators plan to determine the high-resolution structure of KCC2 with the intention of developing strategies to regulate its activity.

Imbalances in excitatory versus inhibitory postsynaptic signaling in the central nervous system (CNS) have been associated with autism spectrum disorders (ASD). These imbalances are caused by mis-regulated chloride (Cl-) concentrations in the CNS. The potassium-chloride co-transporter is the key player involved in maintaining the low Cl- concentrations in neurons necessary for proper signaling. KCC2 is thus a potential target for therapeutic strategies aimed at rescuing excitatory/inhibitory imbalances in ASD and other disorders affected by such imbalances. However, targeted therapeutic strategies require detailed knowledge of the drug targets, and currently, there is insufficient biochemical information to target KCC2 using rational approaches.

Alfred George will employ an automated electrophysiology system to elucidate the functional consequences of a large set of SCN2A variants of unknown clinical significance associated with neurodevelopmental disorders, including autism and epilepsy.