Linking Early Neurodevelopment to Neural Circuit Outcomes — Request for Applications

SFARI Mission

The mission of the Simons Foundation Autism Research Initiative (SFARI) is to improve the understanding, diagnosis and treatment of autism spectrum disorders by funding innovative research of the highest quality and relevance.

Background and Objective

The last decade has seen the discovery and functional annotation of numerous high-confidence autism spectrum disorder (ASD) risk genes^1-3. In the time since, much effort has been dedicated to understanding how these genes impact nervous system development. A consensus has emerged that many genes implicated in ASD susceptibility impact early steps in neurodevelopment, such as the timing and execution of neural differentiation, migration and synaptogenesis, with such cellular phenotypes thought to be rooted in altered epigenomic and transcriptomic landscapes^4-9.

In parallel, SFARI has invested in efforts to characterize the impact of ASD risk gene mutation on the neural circuits underlying ASD-relevant phenotypes, with notable advances made in understanding the contribution of peripheral and central circuits to ASD-related sensory atypicalities, motor phenotypes, sleep disruptions and social behavioral deficits, among other phenotypes^10-13.

While progress has been made toward understanding early development and mature functional outcomes in isolation, studies causally linking disruptions of early neurodevelopment to alterations in ASD-relevant neural circuits remain rare. The objective of this RFA is to bridge this critical gap in our understanding of how developmental events impact later processes of circuit formation and function in ASD.

We envision that this RFA will bring together scientists from a range of backgrounds, such as developmental neurobiologists and circuit neuroscientists, to collaboratively conduct thorough characterizations of how early developmental events result in alterations to ASD-relevant neural circuitry in carefully chosen models.

 References

1. Satterstrom, F. et al. Large-scale exome sequencing study implicates both developmental and functional changes in the neurobiology of autism. Cell. 180, 568-584 (2020). PubMed
2. Fu, J. et al. Rare coding variation provides insight into the genetic architecture and phenotypic context of autism. Nat. Gen. 54, 1320-1331 (2022). PubMed
3. Rolland, T. et al. Phenotypic effects of genetic variants associated with autism. Nat. Med. 29, 1671-1680 (2023). PubMed
4. Schafer, S.T. et al. Pathological priming causes developmental gene network heterochronicity in autistic subject-derived neurons. Nat. Neurosci. 22, 243-255 (2019). PubMed
5. Willsey, H.R. et al. Parallel in vivo analysis of large-effect autism genes implicates cortical neurogenesis and estrogen in risk and resilience. Neuron 109, 788-804 (2021). PubMed
6. Paulsen, B. et al. Autism genes converge on asynchronous development of shared neuron classes. Nature 602, 268-273 (2022). PubMed
7. Villa, C.E. et al. CHD8 haploinsufficiency links autism to transient alterations in excitatory and inhibitory trajectories. Cell Rep. 39, 110615 (2022). PubMed
8. Li, C. et al. Single-cell brain organoid screening identifies developmental defects in autism. Nature 621, 373-380 (2023). PubMed
9. Munz, M. et al. Pyramidal neurons form active, transient, multilayered circuits perturbed by autism-associated mutations at the inception of neocortex. Cell 186, 1930-1949 (2023). PubMed
10. Golden, C. et al. Disrupted circuits in mouse models of autism spectrum disorder and intellectual disability. Curr. Opin. Meurobiol. 48, 106-112 (2017). PubMed
11. Orefice, L. Peripheral somatosensory neuron dysfunction: emerging roles in autism spectrum disorders. Neuroscience 445, 120-129 (2020). PubMed
12. Monday, H. et al. Circuit-level theories for sensory dysfunction in autism: convergence across mouse models. Front. Neurol. 14:1254297 (2023). PubMed
13. Cording, K. and Bateup, H. Altered motor learning and coordination in mouse models of autism spectrum disorder. Front. Cell. Neurosci. 17:1270489 (2023). PubMed

Please find an extended list of literature describing early developmental phenotypes here.