The听Neuro鈥檚听Azrieli Centre听for Autism Research (ACAR) has awarded grants to three projects that will drive creative and innovative research in hopes of providing more insight into future treatment for autism spectrum disorder (ASD). Each听project will be funded $100,000 for a two-year period.听听
The three projects are:听
Heterogeneity of cerebellar learning rules in Fragile X syndrome听听
Aparna听Suvrathan, with听Jesper听Sj枚str枚m听
鈥淚n spite of the prevalence of ASD, our understanding of its neural basis is very limited,鈥� says听Suvrathan.听鈥淭he cerebellum, best known for its role in motor learning, is an understudied part of the brain that has recently been strongly implicated in the causation of autism. This project will investigate the role of cerebellar learning in a monogenic, highly prevalent form of ASD - Fragile X syndrome. In a collaboration between the Suvrathan and Sj枚str枚m labs, we will explore how cerebellar plasticity is disrupted in a mouse model of Fragile X syndrome, using a novel, high-throughput plasticity mapping technique.鈥澨�
鈥淲e are very grateful to the听Azrieli听Foundation for this ACAR award. It will allow us to develop a new experimental approach and test a new theoretical framework, in order to understand the role of the cerebellum in Fragile X syndrome. We believe that our results will provide important insight that will guide the search for therapies.鈥澨�
Identifying molecular pathways and neural mechanisms underlying rescue effects of lithium in a mouse ASD model of SHANK3听haploin听sufficiency听听
Yang Zhou, with听Guy Rouleau听and听Yeming听Xie听
鈥淩ecent clinical studies report the beneficial effects of lithium treatment in several people affected with the SHANK3 gene, a highly penetrating, monogenic cause of ASD, and a leading predisposition of Phelan-McDermid Syndrome (PMS),鈥� says Zhou. 鈥淗owever, the specific mechanisms by which lithium exerts its behavioral-stabilizing effects under the SHANK3 haploinsufficiency have yet to be identified.鈥澨�
The goals of this project are to evaluate lithium administration on neural and behavioral outcomes in a humanized mouse model of autism with SHANK3 mutation; and to underpin the molecular, cellular, and circuit mechanisms whereby lithium acts through.听
"In a recent conversation with Guy Rouleau, Thomas听Bourgeron, and Boris听Chaumette, we learned the beneficial effects of lithium in several patients with SHANK3 mutation. This is very intriguing, encouraging, and we are thrilled to pursue mechanisms beyond the level of symptomology! We are sincerely grateful to the听Azrieli听Foundation for funding this project, which allows us to revisit and examine the neurobiology of a classical, psychiatric medication with a genetic animal model of autism.鈥澨�
Determine the Role of Netrin-3 in an Autism-Like Neurodevelopmental Disorder听听
Timothy Kennedy, with听Philippe Campeau听
鈥淩ecent findings have identified previously undescribed single polymorphisms in the coding sequence of human netrin-3 in young adults with an Autism-like developmental intellectual disorder,鈥� says Kennedy. 鈥淣etrins are a small family of secreted extracellular proteins that are essential for the development of neural circuits during development. We have recently shown that a closely related member of the netrin family,听netrin-1, is made by neurons in the mature brain and regulates changes in synapse function that are associated with memory formation. Although netrin-3 is also expressed in the developing and adult central nervous system, its functional significance has received almost no attention. Supported by the ACAR Research Award our studies aim to identify the cellular distribution of netrin-3 in the brain, determine the functional importance of these newly identified mutations, and the consequences of disrupting netrin-3 function听in vivo.鈥澨�
鈥淥ur proposed studies aim to discover key molecular mechanisms that underlie the development of deficits in neural function associated with听autism spectrum disorder (ASD). Finding these molecules and understanding these mechanisms will identify new targets for therapeutic treatments that aim to enhance neural function and quality of life for individuals with ASD,鈥� Kennedy says. 鈥淭he ACAR Research Award provides support that is critical to bring the project to fruition and to engage a new generation of neuroscience researchers to focus on ASD.鈥澨�
ACAR听was established in 2017 following a transformational $16-million donation from the听Azrieli听Foundation and aims to advance translational research, training, and knowledge transfer in autism. The听centre听is听working听to demystify the origins of Autism Spectrum Disorder and lead to the development of better diagnostic tools and more effective therapies for people with autism.听
Join us for the 听on Monday, November 4, 2019 for ACAR awardees to present their funded research projects and discuss potential collaborations.听听
