Brain-specific expression of cytomegalovirus immediate early protein 1 disrupts neurodevelopment in mice by inducing neuroinflammation and altering astrocytic metabolism.

Congenital human cytomegalovirus (HCMV) infection is the leading cause of neurodevelopmental disorders in children, including nongenetic sensorineural hearing loss. Previous studies have shown that HCMV immediate early 1 (IE1) protein, also known as IE72, contributes to brain maldevelopment. However, the underlying mechanisms are unclear due to the strict species specificity of cytomegaloviruses (CMVs), limiting animal model study. In the current study, we used CRISPR/Cas9 technology to construct a transgenic mouse model (Rosa26-LSL-IE1^+/-, Camk2ɑ-Cre) specifically and stably expressing IE1 protein in brain. These transgenic mice exhibited impaired spatial working memory, hippocampal neurodegeneration, and proinflammatory activation of brain microglia and astrocytes. Transcriptome sequencing revealed that IE1 protein upregulated genes linked to metabolism and downregulated genes implicated in nervous system development. Furthermore, IE1 alters the lactate production pathway in astrocytes, thereby reducing the energy supply available to neurons. These findings suggest that long-term IE1 protein expression disrupts neurodevelopment by inducing neuroinflammation and uncoupling neurons from metabolic support by astrocytes. These results provide a clear molecular mechanism for neurodevelopmental disorders in infants with congenital HCMV infection.