Dissecting estimation of conductances in subthreshold regimes.

We study the influence of subthreshold activity in the estimation of synaptic conductances. It is known that differences between actual conductances and the estimated ones using linear regression methods can be huge in spiking regimes, so caution has been taken to remove spiking activity from experimental data before proceeding to linear estimation. However, not much attention has been paid to the influence of ionic currents active in the non-spiking regime where such linear methods are still profusely used. In this paper, we use conductance-based models to test this influence using several representative mechanisms to induce ionic subthreshold activity. In all the cases, we show that the currents activated during subthreshold activity can lead to significant errors when estimating synaptic conductance linearly. Thus, our results add a new warning message when extracting conductance traces from intracellular recordings and the conclusions concerning neuronal activity that can be drawn from them. Additionally, we present, as a proof of concept, an alternative method that takes into account the main nonlinear effects of specific ionic subthreshold currents. This method, based on the quadratization of the subthreshold dynamics, allows us to reduce the relative errors of the estimated conductances by more than one order of magnitude. In experimental conditions, under appropriate fitting to canonical models, it could be useful to obtain better estimations as well even under the presence of noise.