J. Elliott Robinson plans to create gene therapies to address cognitive symptoms in neurofibromatosis type 1 (NF1) using a combination of protein engineering methods, CRISPR activation-based approaches to regulate endogenous gene expression and new systemic AAV capsids that freely cross the blood-brain barrier after intravenous administration. The resulting vectors will be tested in NF1 model mice in vivo and disseminated to the larger research community for additional validation.

For individuals carrying a genetic risk factor that inactivates one of two gene copies, as is often the case for mutations in CHD8, amplifying the expression of the remaining functional copy is a potential therapeutic target. In the current proposal, Rebecca Muhle plans to use high-throughput in vitro screening assays to discover compounds that affect the endogenous expression of CHD8 and to subsequently test validated compounds in a mouse model of Chd8 haploinsufficiency.

Michael Hart plans to identify novel roles for known ASD risk genes in regulating GABAergic structural plasticity in the nematode C. elegans. He also plans to use unbiased forward genetic screens to identify novel genes that regulate structural plasticity. Findings from these studies may lead to a better understanding of neuronal and circuit plasticity changes associated with ASD pathogenesis.

The ability to create a detailed map of brain development across embryogenesis is important in understanding its alterations in neurodevelopmental disorders such as autism. Reza Kalhor will establish developmental barcoding technologies to map lineage trees of neurons during embryogenesis and compare them in neurotypical and autism genetic mouse models to better understand the etiology of autism.

Gabriela Rosenblau aims to describe how children with ASD learn about others, how learning strategies are implemented in the brain and how learning strategies predict children’s individual treatment outcomes. By providing precise, computational model-based analyses, this project will help guide more targeted behavioral treatments across the autism spectrum.

Corticostriatal dysfunction has emerged in the past few years as a potential converging pathophysiological mechanism underlying autism. Rui Peixoto will address how the maturation of corticostriatal circuits is affected by early imbalances in network activity using the Shank3 knockout mouse as a model of autism.

The single-neuronal basis and causal underpinnings of joint social behavior are still almost completely unknown, which directly affect our ability to understand and treat disorders with social impairments such as those seen in ASD. Keren Haroush plans to examine the neural and population basis of interactive social behavior and its modulation in a nonhuman primate model using neural recordings and deep brain stimulation.

Renata Batista-Brito will use optical tools, electrophysiology and behavioral assessments in an Mef2C knockout mouse model of autism to determine the developmental role of GABAergic dysfunction in regulating sensory processing of cortical networks and behavior.

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.

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.