Physiopathology of Neuronal Micronetworks

Numerous neurological and psychiatric diseases are caused by dysfunctions of cortical neuronal networks that are often incorrectly assembled during embryological life. Several cutting-edge basic research projects are carried out at Université Côte d’Azur on these diseases, in particular on epilepsy, migraine, mental retardation, intellectual disabilities, Alzheimer's disease and other neuropsychiatric disorders (e.g. autism, hyperactivity). There is an important mass of experimental data about the pathological modifications in the functions of cortical neurons, which have been identified in experimental models of these diseases. These data cover different levels of integration:

• the effects of genetic mutations,
• the dysfunctions of specific molecular complexes and processes (e.g. regulation and expression of ion channels, receptors, transcription factors, etc),
• the modifications in the properties of different neuronal subtypes (neuronal excitability, synaptic transmission, cell morphology),
• the emergent properties of their microcircuits and larger networks (cortical connectivity, excitation-inhibition balance, activity and plasticity of the microcircuits and their connections in larger networks),
• complex behavioral phenotypes.

In order to fully understand the pathological mechanisms and develop therapeutic approaches, it is important to shed light on the dysfunctions at all levels, starting from molecular and cellular features, and identify similarities shared by these diseases and their distinctive properties. A theoretical framework is being developed to integrate the dysfunctions observed at different levels and gain a better understanding of the emergence of various forms of pathological activities in neuronal networks. It is difficult to have a comprehensive view of the huge amount of alterations experimentally identified and it is often not possible to intuitively predict the final effect on the emergent properties of cortical circuits. The theoretical framework developed at Université Côte d’Azur uses mathematical modeling and simulation with sufficient detail to account for the main experimental evidences but it is also sufficiently simple to allow for mathematical analyses and modeling. The multi-level theoretical framework will be used to tackle problems and dysfunctions that are specific to a particular pathology and to insert them in an extended model including different integration levels. There are continuous interactions and feedbacks between the theoretical models and the experimental evidences, and the predictions of the models are experimentally tested.