[Introduction] Congenital Zika virus (ZIKV) infection causes severe neurological complications including microcephaly but its pathogenesis is not well understood and there is no effective intervention. We performed unbiased transcriptomic and proteomic analyses of the embryonic mouse brains of our new congenital ZIKV infection model to study its neuropathogenesis.

[Methods] We infected wild-type mouse embryos in utero with ZIKV at embryonic day (E) 10.5. We performed RNA sequencing (RNAseq) and proteomic analysis of the ZIKV-infected and control bulk mouse brains at E14.5.

[Results] RNAseq analysis identified 74 genes significantly downregulated and 507 genes significantly upregulated in the ZIKV-infected brains compared to controls. Forebrain development was the most enriched functional category among the downregulated genes. Proteomic analysis revealed that the protein products of 29 of the 74 genes were also downregulated in the ZIKV-infected brains. These genes were also enriched for regulators of forebrain development including: 1) proneural gene Neurod2 and its downstream targets; 2) marker and regulator of intermediate neural progenitor cells, Tbr2; and 3) regulators of GABAergic interneuron development, Arx and Dlx2.

[Conclusion] Our proteogenomic analysis implicated specific pathways that regulate neural cell fate and interneuron development as an underlying cause of congenital ZIKV syndrome. Abnormal interneuron development may also contribute to high epileptogenicity of the condition. Our new mouse model and unbiased proteogenomic approach are also expected to help therapy development for congenital ZIKV syndrome and may be applied to studies of other congenital infections.