Studies in individuals with autism and in autism mouse models suggest that alterations in parvalbumin expression in interneurons may represent a unifying molecular hub for autism pathobiology. By manipulating parvalbumin levels in transgenic mice, Beat Schwaller expects to shed new light on the role of parvalbumin-expressing interneurons in autism.

Early ASD diagnosis is crucial for the initiation of behavioral therapies — therapies which often lead to a better outcome for affected individuals. Veerle Somers will identify and characterize novel maternal autoantibodies associated with the development of ASD in offspring. These findings have the potential to uncover predictive and diagnostic biomarkers for ASD and could elucidate novel etiological mechanisms of early impairment of fetal brain development in ASD.

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.

Electroencephalogram (EEG) scalp recordings are one of the most common measures of brain activity, but EEG data lacks cellular resolution. Stefano Panzeri aims to develop new mathematical models based on the principles underlying the theory of neural network dynamics to estimate the activity of specific types of neurons from EEG data. These tools can be used to better track the underlying neuronal processes that contribute to the severity and progression of autism spectrum disorders.

While clinical and pathological studies of individuals diagnosed with ASD have repeatedly implicated the cerebellum in ASD pathogenesis, whole-tissue analyses have not found differences in gene expression between ASD and unaffected cerebellar tissue. Kathleen Millen, in collaboration with Kimberly Aldinger, plans to use state-of-the-art single-cell and bulk tissue RNA sequencing to fully define the molecular and cellular diversity across all cell types within the cerebellum in ASD.

Aberrations of the brain’s myelinated white matter have come to light in autism spectrum disorders (ASDs). Neuroligin 3, an ASD risk gene, is strongly expressed in myelin-forming glial cells. Michelle Monje proposes to assess myelination and myelin plasticity in a neuroligin 3 mutant mouse model to understand how changes in myelin may be involved in the pathophysiology of ASD.

Several lines of evidence suggest that neurogenesis during brain development is disrupted in autism, but the mechanisms are unclear. Jeremy Willsey and Martin Kampmann will leverage advances in stem cell technology and CRISPR-based genetic approaches to understand the intersection between autism risk genes and neurogenesis, with the goal of determining whether common molecular pathways underlie the pathogenesis of autism.

A major challenge for autism research is to establish convergent mechanisms that group apparently distinct genetic etiologies. Through investigation and comparison of transcriptome profiles, Eric Morrow aims to identify genetic and mechanistic points of convergence in cells mutant for UBE3A or NHE6 that underlie autism or social communication.

Bilal Haider plans to measure intact cortical circuit activity during quantifiable sensory and behavioral impairments in Cntnap2 knockout mice — a genetically relevant model of autism spectrum disorder (ASD). Findings from these studies are expected to build a detailed picture of how cortical circuit dysfunctions in an ASD mouse model leads to misperception of the external sensory world.

Autism spectrum disorder (ASD) is diagnosed four times as often in boys compared than girls, but the developmental mechanisms that lead to this male bias have not been elucidated. Jessica Tollkuhn recently identified 13 high-confidence ASD risk genes that exhibited increased expression in two sexually dimorphic brain regions of female mice compared to males. The goal of the current project is to determine if this female bias in expression of ASD risk genes extends to cortical brain regions and is restricted to specific cell types, with the long-term goal of understanding female resiliency to developing ASD.