The thermal adjustment used in neuronal biophysical models is wrong: Here is how to fix it

There is a substantial effort, and cost, invested towards biophysical modeling of brain networks. Practically all biophysical models of voltage-activated conductances use Hodgkin-Huxley (HH) mechanisms obtained at an experimental temperature and adjusted to a modeling temperature. To do so, all models use the temperature correction factor Q10, which is assumed fixed. By performing an analysis of published data of the reaction rates of sodium, potassium, and calcium membrane conductances, we demonstrate: 1) Q10 is indeed temperature dependent; 2) this relationship is quantitatively and qualitatively similar across conductances; and 3) there is a strong effect at low temperatures (< 15 °C). We show that Macro-Molecular Rate Theory (MMRT), originally developed to study enzyme-related reactions outside neuroscience, explains this temperature dependency. MMRT predicts the existence of optimal temperatures at which reaction rates start decreasing as temperature increases, a phenomenon that we also found in the published data sets and was previously ignored. We tested the consequences of using MMRT adjusted reaction rates in the HH model of the squid’s giant axon. The MMRT adjusted model reproduces the temperature dependence of the rising and falling times of the action potential. The model also reproduces these properties for squid species that live in different climates. In a second example, we compared spiking patterns of biophysical models based on human cortical neurons from the Allen Cell Types Database. The original models, calibrated at 34 °C, failed to generate realistic spikes at room temperature in more than half of the tested models, while the MMRT produces realistic spiking in all conditions. We propose that the optimal temperature could be a thermodynamical barrier to avoid over excitation in neurons. While this study is centered in membrane conductances, our results have important consequences for all biochemical reactions involved in neuronal signaling.