Male-Dominant Effects of Chd8 Haploinsufficiency on Synaptic Phenotypes during Development in Mouse Prefrontal Cortex

Robert A. Ellingford, Mizuki Tojo, M. Albert Basson, Laura C. Andreae*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

CHD8 is a high penetrance, high confidence risk gene for autism spectrum disorder (ASD), a neurodevelopmental disorder that is substantially more prevalent among males than among females. Recent studies have demonstrated variable sex differences in the behaviors and synaptic phenotypes of mice carrying different heterozygous ASD-associated mutations in Chd8. We examined functional and structural cellular phenotypes linked to synaptic transmission in deep layer pyramidal neurons of the prefrontal cortex in male and female mice carrying a heterozygous, loss-of-function Chd8 mutation in the C57BL/6J strain across development from postnatal day 2 to adulthood. Notably, excitatory neurotransmission was decreased only in Chd8+/- males with no differences in Chd8+/- females, and the majority of alterations in inhibitory transmission were found in males. Similarly, analysis of cellular morphology showed male-specific effects of reduced Chd8 expression. Both functional and structural phenotypes were most prominent at postnatal days 14-20, a stage approximately corresponding to childhood. Our findings suggest that the effects of Chd8 mutation are predominantly seen in males and are maximal during childhood.

Original languageEnglish
Pages (from-to)1635-1642
Number of pages8
JournalAcs chemical neuroscience
Volume15
Issue number8
DOIs
Publication statusPublished - 17 Apr 2024

Keywords

  • ASD
  • Chd8
  • Development
  • Mouse models
  • Neuronal structure
  • Sex difference
  • Synaptic neurotransmission

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