Conventional measures of intrinsic excitability are poor estimators of neuronal activity under realistic synaptic inputs

Activity-dependent regulation of intrinsic excitability has been shown to greatly contribute to the overall plasticity of neuronal circuits. Such neuroadaptations are commonly investigated in patch clamp experiments using current step stimulation and the resulting input-output functions are analyzed to quantify alterations in intrinsic excitability. However, it is rarely addressed, how such changes translate to the function of neurons when they operate under natural synaptic inputs. Still, it is reasonable to expect that a strong correlation and near proportional relationship exist between static firing responses and those evoked by synaptic drive. We challenge this view by performing a high-yield electrophysiological analysis of cultured mouse hippocampal neurons using both standard protocols and simulated synaptic inputs via dynamic clamp. We find that under these conditions the neurons exhibit vastly different firing responses with surprisingly weak correlation between static and dynamic firing intensities. These contrasting responses are regulated by two intrinsic K-currents mediated by Kv1 and K-ir channels, respectively. Pharmacological manipulation of the K-currents produces differential regulation of the firing output of neurons. Static firing responses are greatly increased in stuttering type neurons under blocking their Kv1 channels, while the synaptic responses of the same neurons are less affected. Pharmacological blocking of K-ir-channels in delayed firing type neurons, on the other hand, exhibit the opposite effects. Our subsequent computational model simulations confirm the findings in the electrophysiological experiments and also show that adaptive changes in the kinetic properties of such currents can even produce paradoxical regulation of the firing output. Author summaryMost action potentials that neurons emit during their lifetime are produced by a dynamic interplay between the synaptic inputs and the intrinsic biophysical properties of the postsynaptic neuron. Activity-dependent or neuromodulatory changes targeting these intrinsic properties effectively regulate intrinsic excitability of the neurons and how they integrate synaptic input into firing output. Electrophysiologists mostly employ current step protocols in whole-cell patch clamp experiments to identify such changes in intrinsic excitability and to estimate the underlying functional consequences. In the present study we investigate the firing output of hundreds of hippocampal neurons under standard current step stimulation and when they are bombarded by simulated synaptic inputs via dynamic clamp. Our experiments show that firing intensity values in the two scenarios exhibit a surprisingly low correlation, hence, static firing responses yield poor predictive power to estimate firing responses under synaptic inputs. We also show in electrophysiological experiments and computer simulations that two voltage-dependent K-currents mediated by Kv1 and K-ir-channels in stuttering and delayed firing type neurons, respectively, play a key role in regulating these differential firing responses.