Why are pyramidal cell firing rates increased with aging, and what can we do about it?
© Yadav et al; licensee BioMed Central Ltd. 2008
Published: 11 July 2008
Through compartment modeling of these neurons, we extract aspects of altered morphology and electrophysiology that are central to age-related deterioration in cognitive function. We explore homeostatic mechanisms that can compensate for this deterioration partially or completely. To quantify homeostatic trade-offs between morphology and electrical function, we have designed morphologic metrics that include spine surface area, numbers of apical and basal dendrites, and volume of the soma, while active channel metrics are characterized by their maximal conductances, kinetics, and spatial distribution. By utilizing the concept of normalized sensitivity [3, 4], the effect of perturbations in these metrics on neuronal function characterized by AP firing rate, somatic input resistance, AP firing rate adaptation, electrotonic lengths, and transfer impedance, is determined in terms of unitless measures (sensitivities). By nature, unitless measures allow direct quantitative comparison between parameters as different as branch diameter (μm) and channel densities (mS/cm2). Our preliminary investigations and experimental evidence of an age related increase in slow Afterhyperpolarization (sAHP) and hyperpolarization activated cation (H) channel densities, suggest several alternative hypotheses regarding altered neuron function with age. The increased sAHP, for example, could reflect a compensatory mechanism acting to minimize the firing rate increases that accompany morphologic change, or it may be an epiphenomemon of altered calcium influx observed in normal aging. Our analytical techniques allow us to predict the functional consequences of these alternatives. We also predict biologically realistic mechanisms, involving combinations of morphologic and active membrane properties, that either subserve altered neuron function, or are compensatory in nature. Using these techniques, we identify compensatory mechanisms that can restore cellular function of aged neurons to normal levels, despite the significant morphologic changes that characterize normal aging.
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