Distinct cellular and transcriptional mechanisms mediate an antioxidant therapeutic response in 22q11-deleted upper layer cortical projection neurons
We characterized cellular and molecular mechanisms underlying the therapeutic response in vitro and in vivo to the antioxidant N-acetyl cysteine (NAC), which in the LgDel 22q11.2 Deletion Syndrome mouse model restores growth and connectivity of upper layer cortical projection neurons (Layer 2/3 PNs) and improves cognitive performance. NAC treatment of primary cultured LgDel L 2/3 PNs does not restore these neurons to a wild type (WT) state. Rather than returning to the bimodal dendrite and axon size distribution seen in WT, LgDel L 2/3 PN dendrite and axon growth in vitro increases unimodally in response to NAC. In parallel, altered expression of 22q11-deleted genes and presumed downstream targets are unchanged. Instead, novel antioxidant defense and neuronal growth genes are differentially expressed: some generally NAC-regulated, others responsive only in the context of 22q11 deletion. Apparently, NAC ameliorates L 2/3 PN developmental pathology without restoring WT cell states or typical expression of mutant genes or their downstream targets. NAC also elicits differential expression of antioxidant defense genes in 22q11-deleted L 2/3 PNs--but not L 5/6 counterparts--in the developing postnatal LgDel mouse cortex, rather than modulating 22q11 genes or downstream targets. These NAC-dependent, L 2/3 PN-selective in vivo cellular and transcriptional changes differ substantially from those in primary culture. Thus, despite some in vitro and in vivo parallels, the NAC therapeutic response that diminishes oxidative stress-related L 2/3 PN circuit and behavioral pathology due to 22q11 deletion has a unique in vivo signature.