SFARI

Dagmar Sternad, in collaboration with Pawan Sinha and Robert Joseph, proposes to experimentally test the Predictive Impairment in Autism hypothesis, which posits that the multifaceted manifestations of autism in several domains have a common core: an impaired ability to make predictions. Focusing on the motor domain, Sternad’s team has developed a suite of novel, child-friendly, virtual games that examine motor performance in interception tasks with different degrees of predictive challenges. They plan to provide a quantitative behavioral characterization of motor-predictive impairments in a genetically defined group of children recruited from the SPARK cohort.

Len Pennacchio will utilize his laboratory’s expertise in high-throughput enhancer screening to experimentally test whether noncoding autism-associated sequence variants alter the function of transcriptional enhancers that normally drive gene expression in the developing brain.

Helen Tager-Flusberg previously developed a standardized protocol for assessing expressive language outcomes in school- and home-based settings in children with autism that produces results comparable to assessments made in a lab or clinic setting. Tager-Flusberg now seeks to apply the success of that work in older children by developing a version of their protocol that can be used by parents to assess language ability in younger children at home.

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.

Pierre Mattar proposes to identify and characterize how chromatin-remodeling enzymes regulate neurogenesis in the developing brain and how dysfunction in these complexes contribute to ASD. Specifically, his team aims to determine how chromatin-remodeling functions are disrupted by ASD-linked mutations in ADNP, a gene that encodes a transcription factor that interacts with chromodomain helicase proteins, and how this affects neural progenitor cell function in the developing mouse neocortex.

John Huguenard has preliminary data to suggest that neuronal axons don't develop normally in two mouse models of ASD that result from maternal immune activation. In the current proposal, Huguenard will test if this is a common feature across ASD mouse models, by assessing axonal structure and function in four additional environmental and genetic models.

Arnold Kriegstein will apply single-cell RNA sequencing technologies to brain tissue samples from individuals with Dup15q syndrome, a genetically defined type of ASD, as well as to cerebral organoids derived from Dup15q-induced pluripotent stem cells. The goal of the project is to identify which cell types are affected by ASD during development and how this impacts mature brain circuits.

The genetic and phenotypic complexity of ASD is thought to, in part, be caused by abnormal gene regulation. Ryan Doan plans to systematically screen for noncoding mutations with the greatest likelihood of impacting gene regulation (i.e., gene promoters, splicing regulators, cis-regulatory elements) using both computational predictions and large-scale functional screening assays. Findings from this project will help to elucidate the mechanistic underpinnings of these ASD risk mutations and provide a functional database for use in the future development of therapeutics.

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.

Haiyuan Yu, Bernie Devlin and Kathryn Roeder aim to develop an experimentally and computationally integrated interactome perturbation screening pipeline and additional analytical methods to study the functional impact of de novo missense mutations in autism.