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Biophysical networks underlying the robustness of neuronal excitability

Final Report Summary - CANALOHMICS (Biophysical networks underlying the robustness of neuronal excitability)

Biological systems are incredibly robust to perturbations, such as environmental changes or genetic mutations. However, the structural bases of this biological robustness are still poorly understood. This project aimed at deciphering the structural bases of the robustness of neuronal activity to genetic perturbations in particular. We focused on midbrain dopaminergic neurons, and studied their response to genetic deletion of ion channels involved in generating their electrical activity. First we showed that, depending on the ion channel that is deleted, midbrain dopaminergic neurons show variable levels of robustness, being almost insensitive to the deletion of SK3 channels but highly sensitive to the deletion of Kv4.3 channels. In order to understand the molecular bases of these differences, we combined our electrophysiological characterization of neuronal function with single-neuron transcriptomic investigation of the changes in ion channel expression. We measured the levels of expression of 60 different mRNAs (including many ion channels) in each neuron, such that the complex high-dimensional relationships in their expression levels can be analyzed. Using advanced mathematical analysis (information theory and algebraic topology), we found that specific ion channels (Nav1.2 SK3, Kv4.3 GIRK2) share strong co-variations in their expression levels, and are genetically coupled with genes defining the dopaminergic metabolism and signaling (TH, DAT, VMAT2, D2 receptor) of midbrain dopaminergic neurons. These results give a first insight, suggesting that midbrain dopaminergic neurons achieve a stable electrical phenotype because the levels of expression of some of their most critical ion channels are coupled with their dopaminergic identity. The analysis of the data corresponding to these same genes in ion channel KO animals (SK3, Kv4.3) will help us to determine how the landscape of expression of ion channels is modified in the midbrain dopaminergic neurons in these animals, and to understand how changes in the mRNA expression landscape can explain the differential robustness of dopaminergic neurons to the deletion of these two ion channels. The results of this project will give important clues about the structural bases of the robustness of neuronal activity to genetic perturbations.