Robustness through variability: ion channel isoform diversity safeguards neuronal excitability

Abstract

Neural circuits are composed of different neuron types that exhibit distinctly different computational properties resulting from the sets of ion channels expressed. Profound insight exists into how neural computations arise from the precise regulation of ion channels (Armstrong et al., 1998; Lai, Jan, 2006; Nusser et al., 2012), how degenerate channel properties support similar computations (Marder, Prinz, 2002; Marder, Goaillard, 2006), and how channelopathies affect brain function (Kullmann, 2010). However, it remains elusive why neurons express many more channels, and isoforms thereof, than required to tune their specific excitabilities. Here, we employ an experiment-theory approach pairing electrophysiology with Drosophila genetics, and mathematical modelling to show that the variance in membrane properties that results from ion channel diversity promotes the robustness of neuron-type specific functions. Specifically, we show that the robustness of flight motoneuron coding properties to internal and external perturbations is significantly enhanced by the diversity of calcium channel splice isoforms expressed. Importantly, increased excitability robustness to perturbations of outward currents or temperature does not require adjustments in calcium channel mean properties. Instead, increases of the variance of calcium channel gating properties that result from channel isoform diversity broaden the dynamic input range the neuron can compute without reaching depolarization block. This broadens our concept of the functional consequences of the tremendous variety and diversity of ion channels expressed in brains. One Sentence SummaryThe variance of calcium channel gating properties is increased by channel isoform diversity and aids neuronal coding and excitability robustness.