Homeostasis of intrinsic excitability in hippocampal neurones: dynamics and mechanism of the response to chronic depolarization

摘要

In order to maintain stable functionality in the face of continually changing input, neurones in the CNS must dynamically modulate their electrical characteristics. It has been hypothesized that in order to retain stable network function, neurones possess homeostatic mechanisms which integrate activity levels and alter network and cellular properties in such a way as to counter long-term perturbations. Here we describe a simple model system where we investigate the effects of sustained neuronal depolarization, lasting up to several days, by exposing cultures of primary hippocampal pyramidal neurones to elevated concentrations (10–30 mm) of KCl. Following exposure to KCl, neurones exhibit lower input resistances and resting potentials, and require more current to be injected to evoke action potentials. This results in a rightward shift in the frequency-input current (FI) curve which is explained by a simple linear model of the subthreshold I–V relationship. No changes are observed in action potential profiles, nor in the membrane potential at which action potentials are evoked. Furthermore, following depolarization, an increase in subthreshold potassium conductance is observed which is accounted for within a biophysical model of the subthreshold I–V characteristics of neuronal membranes. The FI curve shift was blocked by the presence of the L-type Ca2+ channel blocker nifedipine, whilst antagonism of NMDA receptors did not interfere with the effect. Finally, changes in the intrinsic properties of neurones are reversible following removal of the depolarizing stimulus. We suggest that this experimental system provides a convenient model of homeostatic regulation of intrinsic excitability, and permits the study of temporal characteristics of homeostasis and its dependence on stimulus magnitude.