Evaluating molecular changes in the brain of Chd8 mutant mice as a function of age

  • Awarded: 2018
  • Award Type: Director
  • Award #: 627144

Genetic risks for autism are diverse and encompass mutations and copy number variations in hundreds of genes. Transcriptional studies suggest autism spectrum disorder (ASD) can also be defined by a shared molecular pathology.

Mark Zylka’s laboratory generated a mutant mouse line with an ASD-linked loss-of-function mutation in Chd8 (V986*; stop codon mutation). Research with autism model mice typically focuses on embryonic, early postnatal and young-adult time points. Yet preliminary studies of this mouse model, which were funded in part by a previous SFARI award, found that both histological changes and behavioral phenotypes worsened with age, suggesting that age is a critical variable to include in studies of autism mouse models.

In the current project, Zylka’s team plans to extend these preliminary studies and further examine the extent to which molecular phenotypes worsen with age in Chd8V986*/+ heterozygous mice. These studies will focus on assessing histological changes in the cerebral cortex, particularly those related to neuroinflammation (e.g., signs of astrocyte or microglia activation) and neurodegeneration, at 12 and 24 months of age. RNA-seq analyses will also be performed to investigate early-life and aged-related transcriptional differences.

Results from these studies are expected to highlight the importance of studying ASD model mice across the lifespan, in order to have a better understanding of how early neurodevelopmental deficits cause cascading brain and behavioral abnormalities later in life.

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