Behavioral abnormalities, cognitive impairments, synaptic deficits, and gene replacement therapy in a CRISPR engineered rat model of the Cri du Chat syndrome-associated 5p15.2 deletion

The Cri du Chat Syndrome (CdCS), an untreatable genetic disorder, arises from a deletion on chromosome 5p. It manifests in distinct features, including a cat-like cry, facial abnormalities, microcephaly, and severe psychomotor/mental retardation. Lack of accurate animal models hinders research. We created a rat model with a similar deletion on chromosome 2q22 using CRISPR-Cas9, replicating CdCS's genetic aberration. This model exhibits deficits in social behavior, cognition, and anxiety. Our innovative gene replacement using AAV-Ctnnd2 via intravenous injection during early development mitigates cognitive impairments but not sociability or anxiety in CdCS rats. This study paves the way for gene therapy to tackle CdCS challenges. Overall design: We collected samples from both hippocampus and prefrontal cortex of rats, including wild type (WT), CdCS genotype, and samples treated with adeno-associated virus (AAV) vectors. Specifically, we are interested in the impact of AAV-mediated gene delivery on gene expression, particularly with the AAV-Ctnnd2 vector. Each condition is represented by four biological replicates. Sample processing involved polyA RNA selection, focusing on mRNA sequencing. All samples were sequenced using paired-end reads on the Illumina Novaseq platform.