Evaluation of the impact of viral neuroinfections on synaptic plasticity and neurodevelopmental disorders

Viral infections during gestation have been proposed as an environmental risk factor to develop neurocognitive and neurodevelopmental disorders, such as Autism Spectrum Disorder (ASD). While the causes are highly multifactorial, the mechanistic origin of these diseases lay into the misregulation of synaptic homeostasis. Indeed, the central nervous system (CNS) exhibits greatly ordered neural circuitry, allowing electrical activity propagation through synaptic buttons for information delivered at high speed. However, minor changes in synaptogenesis and synaptic plasticity can have massive functional impact, and wile this is well-established for ASD and neurocognitive disorders, the contribution of viral neuroinfections and chronic/acute viro-induced neuroinflammation remains obscure. In the EviSyp project, we propose to use advanced 3D multicellular brain models - 1) human cerebral organoids derived from stem cells coming from children without neurological conditions, presenting various degrees of ASD, or Congenital Zika Syndrome (CZS), and 2) organotypic cultures of adult human brain explants - to study the impact of five emerging neurotropic viruses on synaptogenesis, electrical activity, neuroinflammation and epigenetic hallmarks. Given the complexity of these 3D models and the massive amount of data that will be generated, we will use advanced bioinformatic tools to analyze common and specific viro-induced pathways responsible for neurological perturbations and develop a dedicated machine learning framework to predict and score the neurological impact of infections of known/unknown nature. Together, the EviSyp project will provide seminal mechanistic and conceptual information regarding the tripartite interactions between viral neuroinfections, synaptic dysfunctions and neurocognitive/developmental disorders, and improve our preparedness to future pandemics through the development of relevant new resources and tools.