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.
In this pilot study, Pierre Vanderhaeghen and his team aim to explore the intricate connections between ASD, mitochondrial function, and human neuronal development, with a specific focus on developmental timing. Innovative tools, including an in vitro model for studying mitochondrial morphology, dynamics, and function and an in vivo xenotransplantation model of human cortical neurons, will be used to achieve this. The investigation seeks to understand how mitochondrial dynamics and metabolism contribute to the pathology of ASD-linked mutations in genes such as MECP2 and SYNGAP1.
One of the challenges in assessing rodent models of autism/intellectual disability is linking specific genetic alterations to changes in neural function and behavior. Paul Dudchenko plans to address this challenge by using the head direction cell system — comprised of neurons that encode direction — to characterize rigid and flexible neural coding in Fmr1, Grin2b and Syngap1 knockout rats. This characterization will provide rich data on both the neural systems and the behavioral capacities of these three rodent models.
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.
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.
SYNGAP1 encodes a neuronal Ras GTPase activating protein and is a significant risk gene associated with autism spectrum disorders (ASDs) and intellectual disability (ID). As many of the genetic mutations in individuals with SYNGAP1-related ID (SRID) lead to decreased SYNGAP1 expression, SRID is an ideal candidate for genetic and antisense oligonucleotide–based therapies that increase SYNGAP1 expression. Leveraging recently discovered regulatory mechanisms of SYNGAP1 expression, Richard Huganir’s team plans to design precision antisense oligonucleotides that increase SYNGAP1 expression and to validate them using human pluripotent stem cell models of SRID. These studies will help to advance the therapeutic potential of antisense oligonucleotide–based treatments for SRID as well as other monogenic forms of ID and ASD.
Gastrointestinal (GI) distress commonly accompanies autism spectrum disorders (ASDs), significantly impacting the quality of life of those affected and their families. Julia Dallman, in collaboration with John Rawls, plans to use zebrafish as an experimental system, since it allows for the GI tract to be imaged and manipulated in live animals. They aim to determine if GI phenotypes in multiple genetic forms of ASD are caused by convergent gut-intrinsic mechanisms. The expected outcomes would open a new field of GI research for ASD that could suggest treatment strategies for managing GI distress in humans.
Shinjae Chung and Ted Abel will assess the neural dynamics of sleep neurons in Syngap1 mutant mice, aiming to understand how changes in their activity lead to sleep disturbances and behaviors associated with autism.
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.
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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