Hirofumi Morishita plans to identify common corticothalamic circuitry deficits in genetic mouse models of autism that affect social behaviors and establish preclinical strategies for ameliorating these social deficits.

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.

Sensory hypersensitivity is a central issue in autism and autism-related disorders like fragile X syndrome but relatively little is known about the underlying brain mechanisms. In this project, Richard Salvi plans to combine the use of novel behavioral assays for assessing sound hypersensitivity in rats with state-of-the-art electrophysiological and analytical techniques to determine the nature of auditory perceptual and circuit abnormalities in a rat model of fragile X syndrome.

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.

Noninvasive neuroimaging, such as fMRI, has provided insights into dysfunction of large-scale neural systems in ASD and its relationship to cognitive deficits, yet it is unclear how such biomarkers relate to cellular and synaptic features of human brains. To help bridge this gap, John Murray and Alan Anticevic will utilize existing ASD neuroimaging data sets to provide insight about: (i) cortical circuit alterations in a mechanistic computational model, (ii) brain-behavior relationships across individuals and (iii) brain-wide patterns of gene expression in ASD.

Jun Hee Kim will investigate how Scn2a expression in oligodendrocytes contributes to myelination and neural connectivity during brain development in mice and determine whether loss of oligodendroglial Scn2a impacts social and cognitive behaviors relevant to autism. Understanding how deficits in Na_v1.2-mediated oligodendroglial excitability and adaptive myelination could contribute to autism may generate new potential therapeutic strategies for treating this disorder.

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.

Linda Wilbrecht proposes that an inability to appropriately update behavior based on probabilistic feedback represents a core learning deficit in ASD and that specific frontal-striatal circuits may contribute to these deficits. She will test these ideas in two genetic mouse models of ASD to help determine if ASD risk genes affect specific forms of learning and/or specific cell types more than others.

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.