Modeling stress-induced adaptations in Ca2+ dynamics

A hippocampal stress response is mediated by the glucocorticoid and mineralocorticoid receptors and involves primarily delayed changes in hippocampal neuronal properties. In this study, we concentrate on stress-induced effects in CA1 neurons which include an enhancement of the slow afterhypolarization (sAHP), an increase in Ca2+ currents, specifically a presumed upregulation of the Cav1.2 subunit that mediates one type of the L-type Ca2+ currents (the Ls type), and a suppression of Ca2+ extrusion mechanism, manifested as a decrease in plasma membrane Ca2+-ATPase-1. The aim of our study lies in identifying a causal relationship between either or both of the changes in the Ca2+ dynamics system and the increase in the sAHP. We used a compartmental CA1 pyramidal neuron model that included detailed structural properties and biophysical mechanisms and was implemented in the NEURON simulation environment. The model incorporated equations for 16 types of ionic mechanisms, known to be present in CA1 pyramidal cells. Among these, both types of L-type Ca2+ current, one with normal activation kinetics (Ls) and one with additional prolonged openings (Lp), Ca2+-activated K+ conductances that underlie the AHP (IsAHP), and an integrated modeling equation for intracellular Ca2+ decay comprising all Ca2+ extrusion and buffering mechanisms were included. We found that the enhancement of sAHP could be explained partially not by an increase in Ls Ca2+ current, but rather by a decrease in the rate of intracellular Ca2+ decay. Furthermore, we suggest that an additional 50% increase in the IsAHP, along with the change in the Ca2+ extrusion mechanism, could fully explain the experimental findings. Previous modeling work from our lab suggested that there might be a causal effect between an increase in the Lp Ca2+ current and the aging-induced enhancement of the sAHP. However, a respective causal relationship between an increase in the Ls Ca2+ current and sAHP enhancement does not seem to exist, probably due to their differential contribution to intracellular Ca2+ levels. Experimental and computational evidence imply that aging and stress may induce different Ca2+-dependent cellular adaptations in CA1 neurons, which however, result in a similar phenotype of enhanced sAHP and subsequent decreased neuronal excitability.