Linking Prenatal Inflammation to Synaptic Dysfunction in Psychiatric Disorders

Background Maternal exposure to viral infections during pregnancy is a robustly verified risk factor for the future development of neurodevelopmental disorders, including Schizophrenia (SCZ) and Autism Spectrum Disorder (ASD). Our recent study showed severe maternal SARS-CoV-2 infection resulted in post-infection maternal elevation of serum cytokines, IL-6 and IL-17, and was associated with: significant DNA methylation changes in synaptic genes in their infants at birth; and delayed neurodevelopment at 12 months. This suggested a link between maternal immune activation (MIA), synaptic dysfunction and altered neurodevelopment. Aims & Objectives 1. To investigate the relationship between maternal immune activation (MIA) during pregnancy and the development of neurodevelopmental disorders such as Schizophrenia (SCZ) and Autism Spectrum Disorder (ASD), with a specific focus on the role of cytokines (IL-6, IL-17). 2. To analyze the molecular mechanisms underlying neurodevelopmental disruption by studying the effects of pro-inflammatory cytokines on human pluripotent stem cell-derived neuronal cultures, specifically focusing on synaptic genes and receptor expression. 3. To identify molecular targets for precision medicine by uncovering pathways disrupted by prenatal immune activation and examining their relevance in adult psychiatric disorders, particularly SCZ and Major Depressive Disorder (MDD). Method Using single-nuclei RNA sequencing, we also assessed, post-mortem prefrontal cortical tissue from adults diagnosed with SCZ (n=17), Major Depressive Disorder MDD (n=19) and healthy controls (n=18). Pathway analysis revealed postsynaptic and cell-projection alterations, particularly within the glutamatergic synapse. Investigating causal relationships, we tested the direct effect of pro-inflammatory cytokines (IL-6, IL-17, IL-1b, TNF, cytokine storm (all cytokines) on human pluripotent stem cell hPSC-derived neuronal cultures at the neural progenitor stage and a mature neuronal stage (DIV 50), with targeted molecular profiling of synaptic and neurodevelopmental markers. Results We show dynamic transcriptional changes in developmental genes and cell proliferation when exposed to cytokines at the progenitor stage. Subsequently, synaptic genes, glutamatergic and GABAergic receptors were disrupted in the mature cytokine exposed cultures. Notably, we observed a remarkable convergence between the SARS-CoV-2 exposed infant data, the cytokine-treated cultures and post-mortem adult patient data. Discussion & Conclusions This pioneering study, incorporating data sets from the cradle to the grave, evidenced a critical link between prenatal inflammation and the synaptopathy observed in certain psychiatric disorders and revealed novel molecular targets amenable to precision-medicine interventions.