Voltage-gated K-currents facilitate differential regulation of intrinsic excitability and synaptic integration

01/29/2020

Adrienn Szabó¹, Katalin Schlett¹, Attila Szűcs^1, 2

¹ Neuronal Cell Biology Research Group, Department of Physiology and Neurobiology, Eötvös Lóránd University, Budapest,

Intrinsic excitability of neurons is commonly investigated in electrophysiological experiments based on intracellular injection of step currents. It is less understood how measures of static excitability, as observed in such experiments translate to the firing of the same neurons when they integrate complex synaptic inputs. We have recently shown that firing responses observed under constant current injection provide poor estimation for the intensity of synaptic responses in a variety of neuron types. Indeed, the correlation between measures of static vs. dynamic excitability of cultured hippocampal neurons turned to be surprisingly low. In the next set of experiments, we pharmacologically manipulated the dendrotoxin-sensitive K-current and the inward rectifying K-current in hippocampal neurons and confirmed the major role of these two voltage-gated currents in the differential regulation of the firing output. Here, we extend this investigation by performing a comprehensive computational modeling study to identify the key biophysical properties that facilitate the differential effects observed in the biological experiments. First, by randomly varying the maximal conductances of specific voltage-gated currents in model neurons we manage to reproduce the physiological diversity of hippocampal neurons as observed in the patch clamp data. Next, we reproduce the effects of pharmacological blocking of the D- and Kir-currents and show that these 2 currents play a major role in setting the dynamical behavior of the stuttering and delayed firing type neurons. As the most intriguing result, we show that changes in the kinetic parameters of the D-current reshape the firing responses of the neurons in a dramatic manner. Effectively, even a slight increase of the activation speed of the D-current can boost the firing output of the stuttering neurons under current steps, while moving the intensity of the synaptic responses in the opposite direction. These findings provide a sound explanation for the electrophysiological data and help to gain a better understanding of the functional impact of the neurons’ intrinsic K-currents.This work was completed by the National Brain Research Program (2017-1.2.1-NKP-2017-00002) and by the ELTE Institutional Excellence Program supported by the National Research, Development and Innovation Office (NKFIH-1157-8/2019-DT).