Frequency‐dependent regulation of intrinsic excitability by voltage‐activated membrane conductances, computational modeling and dynamic clamp

: As one of the most unique properties of nerve cells, their intrinsic excitability allows them to transform synaptic inputs into action potentials. This process reflects a complex interplay between the synaptic inputs and the voltage-dependent membrane currents of the postsynaptic neuron. While neurons in natural conditions mostly fire under the action of intense synaptic bombardment and receive fluctuating patterns of excitation and inhibition, conventional techniques to characterize intrinsic excitability mainly utilize static means of stimulation. Recently, we have shown that voltage-gated membrane currents regulate the firing responses under current step stimulation and under physiologically more realistic inputs in a differential manner. At the same time, a multitude of neuron types have been shown to exhibit some form of subthreshold resonance that potentially allows them to respond to synaptic inputs in a frequency-selective manner. In this study, we performed virtual experiments in computational models of neurons to examine how specific voltage-gated currents regulate their excitability under simulated frequency-modulated synaptic inputs. The model simulations and subsequent dynamic clamp experiments on mouse hippocampal pyramidal neurons revealed that the impact of voltage-gated currents in regulating the firing output is strongly frequency-dependent and mostly affecting the synaptic integration at theta frequencies. Notably, robust frequency-dependent regulation of intrinsic excitability was observed even when conventional analysis of membrane impedance suggested no such tendency. Consequently, plastic or homeostatic regulation of intrinsic membrane properties can tune the frequency selectivity of neuron populations in a way that is not readily expected from subthreshold impedance measurements.