SYNAPTIC TRANSMISSION AND THE THERAPEUTIC POTENTIAL OF GENETIC RESCUE IN A MOUSE MODEL OF CHD8 HAPLOINSUFFICIENCY

Loss-of-function mutations in chromodomain helicase DNA-binding protein 8 (CHD8) are a strong risk factor for neurodevelopmental conditions such as autism and intellectual disability. CHD8 encodes a chromatin remodeler that regulates gene expression, with targets including other autism risk genes. Despite its clinical relevance, the cellular mechanisms linking CHD8 dysfunction to altered neural circuit formation are not yet fully understood.
Previous studies in mouse models of Chd8 haploinsufficiency have shown that synaptic function is altered in the prefrontal cortex (PFC), a region that has been implicated in autism. Here, using whole-cell patch clamp electrophysiology, we show that this phenotype is both region- and layer-specific, as synaptic transmission is largely unaffected in superficial layers of the PFC and in the hippocampus of Chd8+/- mice.
In order to determine whether the synaptic phenotypes can be rescued by restoring Chd8 levels postnatally, we developed a strategy to upregulate the expression of the remaining functional Chd8 allele using CRISPR activation (CRISPRa). We describe the design and ongoing validation of CRISPRa constructs targeting the Chd8 promoter.
Overall, this work integrates phenotypic characterisation with genetic intervention to evaluate the potential of CRISPRa to rescue Chd8-related synaptic changes.