The Effects of Maternal Immune Activation on the Phospho-Proteome of the Developing Adolescent Mouse Hippocampus

Background Prenatal infection may induce neuroinflammation in the developing foetus, which impacts neurodevelopment and predisposes emergence of neuropsychiatric disorders such as schizophrenia in adolescence. In our influenza-based prenatal infection (maternal immune activation, MIA) mouse model, we previously characterised schizophrenia-relevant structural, morphological, and gene expression abnormalities in adolescent MIA offspring. Proteomic investigation recently showed that normally sexually dimorphic immunoregulatory proteins are centrally dysregulated in the hippocampus of late adolescent female MIA offspring. Based on these findings and previous reports, further dysregulation of protein phosphorylation was suspected. Aims & Objectives We sought to investigate phospho-proteomic hippocampal changes in mouse MIA offspring during adolescence. We hypothesised that female MIA offspring would exhibit an upregulation of phospho-proteins compared to controls, relevant to synaptic plasticity, intracellular signalling, metabolism, and inflammation pathways. Method Pregnant C57BL/6J dams were incubated with either influenza or saline control. Their female and male offspring were raised to late adolescence (8-weeks of age) and young adulthood (14-weeks), before hippocampal excision. Hippocampus samples were prepared for phospho-proteomic analysis with 18-plex tandem mass tag and liquid chromatography-facilitated mass spectrometry (LC-MS/MS). Bioinformatic analysis was performed using a phospho-proteomics-modified Searchlight pipeline. Results We discovered several sex-specific phospho-proteomic changes in MIA adolescent hippocampi, and female-specific changes in adult MIA hippocampi, suggesting a female susceptibility to phospho-proteomic dysregulation in MIA offspring. Almost all significant phospho-proteins were upregulated. These included Ank1, Arhgap5, Arhgap21, Camk2b, Cldn11, Jph3, Mbp, Speg, and Tmcc2. Discussion & Conclusions These findings highlight the sexually dimorphic dysregulation of specific phosphorylated proteins, which consist largely of postsynaptic proteins. These play important roles in synaptic plasticity, cytoskeletal structure, inflammation, cell signalling, and cell metabolism pathways, and may contribute to functional impairments in the hippocampus of MIA offspring. Pharmaceutically targeting these phosphorylation pathways may have therapeutic benefit in neurodevelopmental disorders like schizophrenia.