ION CHANNEL DEGENERACY AND NEURONAL MORPHOLOGY ENHANCE EXCITABILITY ROBUSTNESS IN <EM >DROSOPHILA</EM> FLIGHT MOTONEURONS

Neural circuits are composed of distinct neuron types with complex morphologies and ion channel repertoires, resulting in specific computational properties. It remains elusive how neurons harness this complexity, since simplified point-neurons with few ion channels can reproduce diverse excitabilities. Here, we employ an experiment-theory approach pairing in situ patch clamp with Drosophila genetics, and mathematical modelling to show how molecular degeneracy, i.e. structurally different components with similar functions, safeguards neuronal excitability. Specifically, we demonstrate an experimental manipulation of ion channel degeneracy by targeted reduction of voltage gated calcium channel (VGCC) splice isoform diversity in Drosophila flight motoneurons. Importantly, we show that the increased excitability robustness to perturbations (potassium channel blockade, temperature) does not require adjustments of mean calcium current properties, but an increased variance of gating properties resulting from VGCC isoform diversity. Putting this into a theoretical framework, we developed a mathematical reformulation that treats degeneracy as an explicit parameter, allowing us to separate the stabilizing effects of VGCC isoform diversity from the mean calcium current. Having this tool in hand, we artificially increased the variance, i.e. isoform variability, via dynamic clamp to rescue firing activity in a splice variant-reduced scenario. Besides the stabilizing effect of ion channel degeneracy on excitability robustness, severe reduction of total dendritic length to increase the coupling between the somato-dendritic region and the axonal segment renders excitability less robust to perturbation of outward currents. Taken together, this broadens our understanding for the functional consequences of ion channel diversity and complex dendritic morphologies in the brain.