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.

Jeremy Veenstra-VanderWeele and colleagues plan to probe the relationship between maternal serotonin levels and neurodevelopmental phenotypes in offspring by assessing serotonin levels in existing maternal blood samples from the Simons Simplex Collection as well as previously collected placental and cord blood samples from a South African cohort.

Converging lines of evidence suggest that dendritic spine pathology is a common feature in ASD. Alex Kwan will use advanced optical imaging methods in awake behaving mice to determine how calcium signaling in dendritic spines is affected by ASD-linked genetic mutations.

Maria Chahrour plans to assess, in both human tissue and mouse models, whether derepression of L1Hs retrotransposon activity plays a role in the pathobiology of ASD. This initiative will establish a new potential etiology for ASD, supporting fresh opportunities for diagnosis and treatment.

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.

Yun Li will investigate the effects of candidate ASD genes on neural and glial development and on cell-cell communication using human stem cell-derived 2-D neural cultures and 3-D brain organoids.

Genetic studies of ASD implicate alterations in synaptic development and signaling, with the synaptic protein neurexin-1 playing a pivotal role. Ann Marie Craig aims to develop new approaches to overcome neurexin-1-linked synaptic deficits in ASD by modulating the remaining NRXN1 allele to boost neurexin-1 function and restore synaptic structure and function.

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.

Jonathan Mill’s project aims to characterize multiple layers of gene regulation during brain development, facilitating a systematic exploration of hypotheses related to the neurodevelopmental origins of autism. Further, by characterizing genetic effects on gene regulation during neurodevelopment, this work will facilitate the interpretation of genetic findings for autism.