SFARI Funds 5 Projects Aiming To Understand Early Neural Circuit Development in Autism

The Simons Foundation Autism Research Initiative (SFARI) and Simons Foundation International are pleased to announce the funding of five projects investigating the influence of autism-associated risk genes on early neurodevelopment and links to later circuit-level functional outcomes. These awards will provide up to $3.6 million over 4 years to each team of researchers and will be funded by Simons Foundation International and administered by the Simons Foundation.

“There has been a critical gap in studies linking changes in early neurodevelopmental processes to later impacts on neural circuit function and behavior,” says Executive Vice President of Autism and Neuroscience Kelsey Martin. “We look forward to supporting these talented groups as they work to connect autism-relevant phenotypes across developmental time and biological scales.”

The funded projects are:

Longitudinal in vivo CRISPRi screen for abnormal molecular and circuit maturation of intratelencephalic cortical neurons in ASD

PIs: Denis Jabaudon, M.D., Ph.D., University of Geneva (Lead PI); Rosa Cossart, Ph.D., Institut National de la Santé et de la Recherche Médicale in France
This study aims to investigate the maturation of intratelencephalic (IT) neurons in the cerebral cortex, a cell type implicated in autism-related dysfunctions. Using in vivo longitudinal imaging and genetic approaches, the research will explore how different genes affect IT neuron development and circuit formation.

Linking human-specific synaptic developmental timing to early cortical circuit function and plasticity in autism spectrum disorders

PIs: Pierre Vanderhaeghen, M.D., Ph.D., Vlaams Instituut voor Biotechnologie, Belgium (Lead PI); Vincent Bonin, Ph.D. Vlaams Instituut voor Biotechnologie, Belgium; Franck Polleux, Ph.D., Columbia University
This project will leverage studies of human cortical neurons xenotransplanted in the mouse cortex as well as mouse models of humanized expression of human-specific genes to determine how accelerated synaptic developmental timing found in SYNGAP1 mutant cortical neurons leads to alterations in early cortical circuit function, plasticity and behavior.

Primary and compensatory effects of ASD gene mutations on the development of cortical and corticostriatal circuits

PIs: Daniel Feldman, Ph.D., University of California, Berkeley (Lead PI); Helen Bateup, Ph.D., University of California, Berkeley; Linda Wilbrecht, Ph.D., University of California, Berkeley
This collaboration will investigate a “dual-hit” model in which highly penetrant autism-related gene mutations cause both a primary disruption of early circuit development and impair or saturate homeostatic processes to prevent effective compensation.

Early neuron dysfunction in emergent MEF2C haploinsufficiency phenotypes

PIs: Michael Greenberg, Ph.D., Harvard University (Lead PI); Sandeep Robert Datta, M.D., Ph.D., Harvard University
This project aims to causally link disruptions in early neuron development caused by mutations in MEF2C, a gene strongly associated with autism and related neurodevelopmental disorders, to subsequent autism-relevant circuit and behavioral dysfunction.

Understanding how altered sensory experience shapes social decision-making in autism spectrum disorder

PIs: Lauren Orefice, Ph.D., Massachusetts General Hospital (Lead PI); Christopher Harvey, Ph.D., Harvard University
The goal of this project is to identify the potential mechanisms through which altered sensory experiences, caused by peripheral sensory neuron dysfunction, lead to altered social behaviors in mouse models for autism.