Mild membrane depolarization in neurons induces immediate early gene transcription and acutely subdues responses to successive stimulus

Abstract

The transcriptional profile of immediate early genes (IEGs) is indicative of the duration of neuronal activity, but it is unknown whether it affected by the strength of depolarization. Also unknown is whether an activity history of graded potential changes influences further neuronal activity. In this work with dissociated rat cortical neurons, we found mild depolarization – mediated by elevated extracellular KCl – not only induces a wide array of rapid IEGs, but also transiently depresses transcriptional and signaling responses to a successive stimulus. This latter effect was independent of de novo transcription, translation, calcineurin (CaN) signaling, and MAPK signaling downstream of PKC. Furthermore, as measured by multiple electrode arrays, mild depolarization acutely subdues subsequent spontaneous and bicuculline-evoked activity. Collectively, this work suggests that a recent history of graded potential changes acutely depresses neuronal intrinsic properties and subsequent responses. Such effects may have several potential downstream implications, including reducing signal-to-noise ratio during Hebbian plasticity processes.

Merits and Limitations of Studying Neuronal Depolarization-Dependent Processes Using Elevated External Potassium

“…This does not bring the resting membrane potential to zero, but it is sufficient to induce robust gene expression. We have found that lower concentrations of KCl (mild depolarization) are also potent inducer of neuronal IEG transcription ( Rienecker et al., 2020 ). Treatment times also vary widely, from 10 seconds to 48 hours.…”

“…However, to our knowledge, there has not been a methodical investigation into whether varied concentrations and treatment times interact to produce different gene expression profiles. We might expect variation, as different concentrations of intracellular Ca 2+ and modes of Ca 2+ entry differentially induce different signaling pathways, resulting in distinct transcriptional profiles ( Rajadhyaksha and Kosofsky, 2005 ; Tyssowski et al., 2018 ; Rienecker et al., 2020 ). In Table 1 , we have compiled and sorted selected papers by KCl concentration and time of treatment.…”