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.

Autism spectrum disorders (ASDs) are highly heterogeneous neurodevelopmental conditions. Beate St Pourcain aims to disentangle autism heterogeneity by identifying shared and unique genetic factors among co-occurring ASD symptoms.

Anis Contractor will assess how the development of synapses and circuits in the striatum are disrupted in a novel mouse model of autism that harbors a gain-of-function mutation in the voltage-gated calcium channel Cav1.3 in order to gain an understanding of how this mutation contributes to autism risk.

Hisashi Umemori will use knockout mouse models to identify the roles played by a group of ASD-linked protocadherins in regulating specific cortico-striatal circuits, aiming to reveal novel molecular and circuit mechanisms underlying the pathophysiology of ASD.

Denis Jabaudon aims to trace abnormal developmental trajectories of neocortical progenitors and their progeny in a 22q11.2 deletion syndrome mouse model in order to identify potential developmental hot spots amendable to therapeutic interventions for ASD.