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Zika virus (ZIKV) is a kind of flavivirus emerged in French Polynesia and Brazil, and has led to a worldwide public health concern since 2016. ZIKV infection causes various neurological conditions, which are associated with fetus brain development or peripheral and central nervous systems (PNS/CNS) functional problems. To date, no vaccine or any specific antiviral therapy against ZIKV infection are available. It urgently needs efforts to explore the underlying molecular mechanisms of ZIKV-induced neural pathogenesis. ZIKV favorably infects neural and glial cells specifically astrocytes, consequently dysregulating gene expression and pathways with impairment of process neural cells. In this study, we applied a model for ZIKV replication in mouse primary astrocytes (MPAs) and profiled temporal alterations in the host transcriptomes upon ZIKV infection. Among the RNA-sequencing data of 27,812 genes, we examined 710 genes were significantly differentially expressed by ZIKV, which lead to dysregulation of numerous functions including neurons development and migration, glial cells differentiation, myelinations, astrocytes projection, neurogenesis, and brain development, along with multiple pathways including Hippo signaling pathway, tight junction, PI3K-Akt signaling pathway, and focal adhesion. Furthermore, we confirmed the dysregulation of the selected genes in MPAs and human astroglioma U251 cells. We found that PTBP1, LIF, GHR, and PTBP3 were upregulated while EDNRB and MBP were downregulated upon ZIKV infection. The current study highlights the ZIKV-mediated potential genes associated with neurodevelopment or related diseases. Author summary: Zika virus (ZIKV) infection causes serious neurological disorders of central and peripheral nervous system, and fetal brain development disorders including microcephaly. There are still uncovered explorations for the underlying molecular mechanism of ZIKV-infected pathogenesis. This study reveals a series of dysregulation of neuropathic genes mRNA and protein expression in mouse and human astrocytes upon ZIKV infection. As an ideal ZIKV infection model in mouse primary astrocytes (MPAs), RNA-seq was performed to profile transcriptome alteration by ZIKV infection. Bioinformatics analysis demonstrated the significant alterations of the 710 genes that were linked to glial cell differentiation and projection, neurogenesis and migration of neurons, myelination, as well as synaptic control. Among the top selected differentially expressed genes, such as PTBP1, LIF, GHR, PTBP3, EDNRB, and MBP, the mRNA and protein expressions were confirmed to identify the dysregulation of the transcriptome in MPAs upon ZIKV infection. Furthermore, ZIKV infection altered the mRNA and protein expression of these astrocytic genes involved in neurodevelopment in U251 cells following the analysis of the transcriptome. In conclusion, the alteration of astrocytic gene functions or associated-pathways suggest a novel clue of a mechanism involved in the ZIKV-induced neurodevelopment disorders. [ABSTRACT FROM AUTHOR]