Cell-type-specific synaptic imbalance and disrupted homeostatic plasticity in cortical circuits of ASD-associated Chd8 haploinsufficient mice

Robert A Ellingford, Martyna J Panasiuk, Emilie Rabesahala de Meritens, Raghav Shaunak, Liam Naybour, Lorcan Browne, M Albert Basson, Laura C Andreae

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15 Citations (Scopus)
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Abstract

Heterozygous mutation of chromodomain helicase DNA binding protein 8 (CHD8) is strongly associated with autism spectrum disorder (ASD) and results in dysregulated expression of neurodevelopmental and synaptic genes during brain development. To reveal how these changes affect ASD-associated cortical circuits, we studied synaptic transmission in the prefrontal cortex of a haploinsufficient Chd8 mouse model. We report profound alterations to both excitatory and inhibitory synaptic transmission onto deep layer projection neurons, resulting in a reduced excitatory:inhibitory balance, which were found to vary dynamically across neurodevelopment and result from distinct effects of reduced Chd8 expression within individual neuronal subtypes. These changes were associated with disrupted regulation of homeostatic plasticity mechanisms operating via spontaneous neurotransmission. These findings therefore directly implicate CHD8 mutation in the disruption of ASD-relevant circuits in the cortex.
Original languageEnglish
Pages (from-to)3614-3624
Number of pages11
JournalMolecular Psychiatry
Volume26
Issue number7
Early online date9 Apr 2021
DOIs
Publication statusPublished - Jul 2021

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