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 Ca^2^+ currents, specifically a presumed upregulation of the Ca"v1.2 subunit that mediates one type of the L-type Ca^2^+ currents (the Ls type), and a suppression of Ca^2^+ extrusion mechanism, manifested as a decrease in plasma membrane Ca^2^+-ATPase-1. The aim of our study lies in identifying a causal relationship between either or both of the changes in the Ca^2^+ 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 Ca^2^+ current, one with normal activation kinetics (Ls) and one with additional prolonged openings (Lp), Ca^2^+-activated K^+ conductances that underlie the AHP (I"s"A"H"P), and an integrated modeling equation for intracellular Ca^2^+ decay comprising all Ca^2^+ extrusion and buffering mechanisms were included. We found that the enhancement of sAHP could be explained partially not by an increase in Ls Ca^2^+ current, but rather by a decrease in the rate of intracellular Ca^2^+ decay. Furthermore, we suggest that an additional 50% increase in the I"s"A"H"P, along with the change in the Ca^2^+ 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 Ca^2^+ current and the aging-induced enhancement of the sAHP. However, a respective causal relationship between an increase in the Ls Ca^2^+ current and sAHP enhancement does not seem to exist, probably due to their differential contribution to intracellular Ca^2^+ levels. Experimental and computational evidence imply that aging and stress may induce different Ca^2^+-dependent cellular adaptations in CA1 neurons, which however, result in a similar phenotype of enhanced sAHP and subsequent decreased neuronal excitability.