SFARI is pleased to announce that it intends to fund 19 grants in response to the Summer 2020 Pilot Award request for applications.
Based on the critical role of silent synapses in developmental neurocircuit refinement, Oliver Schlüter aims to assess whether ASD-risk genes encoding proteins associated with glutamate receptor complexes play a common role in silent synapse development. Using three different ASD mouse models (Shank3, Syngap1 and Nlgn3 deficiency), Schlüter will assess whether alterations in silent synapse maturation represent a common mechanistic defect underlying the distinct phenotypic facets of ASDs.
In the current project, Arpiar Saunders and his lab plan to determine how variants in the ASD risk genes GRIN2B and SYNGAP1 alter molecular and synaptic properties of mouse somatosensory cortical circuits. To achieve this goal, they will use next-generation viral tools and high-throughput single-cell RNA sequencing that enable highly parallelized connectivity and molecular phenotyping of mouse cells expressing human alleles in the intact brain.
The overall goal of Xin Tang’s project is to yield insights into the molecular programs that lead to reduced KCC2 gene expression in neurons from individuals with autism and to consequently develop mechanism-guided drugs that restore KCC2 gene expression and ultimately reverse symptoms of the condition.
ASD is believed to modify the balance of excitation and inhibition in brain circuits and is frequently accompanied by seizures, but precisely how and why this occurs is poorly understood. In this project, Sacha Nelson and colleagues plan to use an in vitro slice culture platform in combination with calcium imaging techniques to record activity from brain regions important for sensation and memory in four established genetic mouse models of ASD. By studying changes in neuronal and epileptiform activity over development, the progression of brain pathology and the mechanisms that normally compensate for it will be better understood.
Online measures have the potential to provide greater sensitivity to change in longitudinal studies and clinical trials. In the current study, Thomas Frazier and colleagues plan to develop and validate an online evaluation tool that includes: (1) a survey completed by caregivers to better understand behavior and functioning and (2) patient-completed measures that use a webcam to collect gaze and facial expression responses to evaluate thinking skills. If successful, the measures developed could greatly enhance research in autism and related neurodevelopmental genetic syndromes and might one day enhance clinical practice.
Bateup will use genetic mouse models of ASD to investigate the idea that synaptic alterations in the striatum are central to the inflexible behaviors observed in ASD.
Jess Cardin and Michael J. Higley will establish a functional screen (using a CRISPR/Cas9-induced gene disruption system and multiscale in vivo calcium imaging in awake mice) for the assessment of common cellular- and circuit-level cortical dysregulation phenotypes associated with mutations in ASD risk genes.
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