cA2+ influx through voltage-gated Ca2+ channels is essential for neurotransmitter release, synaptic plasticity, electrical waveform processing and modification of gene expression in neurons. Yet Ca2+ can also have harmful effects in neurons; modest, sustained elevation of cytoplasmic Ca2+ concentration leads to neuronal degeneration, and ultimately, cell death. Accumulation of such Ca2+ insults has been hypothesized to underlie at least some aspects of brain aging and dementia. As dominant contributors to neuronal Ca2+ signalling, Ca2+ channels represent major potential targets in the search for sources of aging- related neuronal malfunction. Indeed, it has been established over the last several years that the contribution of voltage-gated Ca2+ channels to electrical activity in neurons changes with aging. The principal goal of Project 2 is to delineate mechanisms of aging-induced alteration in the activity of voltage-gated Ca2+ channels in brain neurons. The research plan is directed towards three specific aims: (1) What biophysical properties of Ca2+ channels change with aging? (2) Does aging dependent alteration of Ca2+ channel activity arise from changes intrinsic to the Ca2+ channel? (3) Does aging-dependent alteration of Ca2+ channel activity result from extrinsic influences? The experimental approach takes of advantage of the ability of patch-clamp electrophysiological techniques to detect critical, but potentially subtile, changes in Ca2+ channel behavior in aging. Properties that may change include (i) amplitude of Ca2+ current, (ii) the voltage-dependencies of channel activation, inactivation and deactivation, (iii) efficiency of channel opening, (iv) Ca2+ permeability through the channel or (v) sensitivity to modulation by neurotransmitter-receptors. All of these parameters will be measured and compared as a function of neuron age. The biophysical and pharmacological work will be complemented by efforts to determine whether channel subunit makeup changes with aging. Tissue and single-cell mRNA analyses will be used as a first step towards this goal. The combined electrophysiological and molecular biological approach will provide a synergistic effort to track down the origins of Ca2+ channel dysfunction related to brain aging. Understanding fundamental mechanisms of Ca2+ channel dysfunction in aging will be vital in developing clinical treatments for brain senescence, and perhaps for such dementias as Alzheimer's disease.
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