An antioxidant therapy elicits distinct transcriptome responses in 22q11-deleted upper layer cortical projection...

We characterized in vitro and in vivo responses to the antioxidant N-acetyl cysteine (NAC) in mice that model the heterozygous deletion of genes at human chromosome 22q11.2 associated with the 22q11.2 deletion syndrome (22q11DS). In this 'large deletion' (LgDel) mouse model, NAC restores the growth and connectivity of developing upper layer cortical projection neurons (L 2/3 PNs) and improves their cognitive performance. It ameliorates L 2/3 PN developmental pathology without restoring wild-type (WT) growth patterns or expression levels of downstream targets of 22q11-deleted genes. Instead, neuronal growth and antioxidant defense genes are differentially expressed when comparing LgDel and WT PNs, i.e. some are generally regulated by NAC, while others are responsive only in the context of 22q11 deletion. NAC also elicits the expression of genes involved in growth and antioxidant defense in differentiating 22q11-deleted L 2/3 PNs in postnatal LgDel mouse cortex rather than restores 22q11 downstream targets to WT levels; however, these L 2/3 PN-selective in vivo changes differ substantially from those in primary culture. Thus, the therapeutic response to NAC that diminishes oxidative stress-related L 2/3 PN developmental circuit and behavioral pathology due to 22q11 deletion has a distinct in vivo signature.