Homeostatic Regulation of Intrinsic Excitability in Hippocampal Neurons

Abstract

The proper functioning of nervous systems requires electrical activity to be tightly regulated. Perturbations in the intrinsic properties of neurons, and in excitatory input, are imposed throughout nervous system development as cell morphology and network activity evolve. In mature nervous systems these changes continue as a result of synaptic plasticity and external stimuli. It is therefore likely that homeostatic mechanisms exist to regulate membrane conductances that determine the excitability of individual neurons, and several mechanisms have been characterised to date. This thesis characterises a novel in vitro model for homeostatic control of intrinsic excitability. The principal finding is that cultured hippocampal neurons respond to chronic depolarisation over a period of days by attenuating their response to injected current. This effect was found to depend on the level of depolarisation and the length of treatment, and is accompanied by changes in both active and passive membrane conductances. In addition, the effect is reversible and dependent on L-type calcium channel activity. Using experimental data to parameterise a conductance-based computer model suggests that the changes in conductance properties account for the observed differences in excitability.