Early and simultaneous emergence of multiple hippocampal biomarkers of aging is mediated by Ca2+-induced Ca2+ release.
ABSTRACT Age-dependent changes in multiple Ca2+-related electrophysiological processes in the hippocampus appear to be consistent biomarkers of aging, and several also correlate with cognitive decline. These findings have led to the hypothesis that a common mechanism of Ca2+ dyshomeostasis underlies aspects of aging-dependent brain impairment. However, some key predictions of this view remain untested, including that multiple Ca2+-related biomarkers should emerge concurrently during aging and their onset should also precede/coincide with initial signs of cognitive decline. Moreover, blocking a putative common source of dysregulated Ca2+ should eliminate aging differences. Here, we tested these predictions using combined electrophysiological, imaging, and pharmacological approaches in CA1 neurons to determine the ages of onset (across 4-, 10-, 12-, 14-, and 23-month-old F344 rats) of several established biomarkers, including the increases in the slow afterhyperpolarization, spike accommodation, and [Ca2+]i rise during repetitive synaptic stimulation. In addition, we tested the hypothesis that altered Ca2+-induced Ca2+ release (CICR) from ryanodine receptors, which can be triggered by L-type Ca2+ channels, provides a common source of dysregulated Ca2+ in aging. Results showed that multiple aging biomarkers were first detectable at about the same age (12 months of age; approximately midlife), sufficiently early to influence initial cognitive decline. Furthermore, selectively blocking CICR with ryanodine slowed the Ca2+ rise during synaptic stimulation more in aged rat neurons and, notably, reduced or eliminated aging differences in the biomarkers. Thus, this study provides the first evidence that altered CICR plays a role in driving the early and simultaneous emergence in hippocampus of multiple Ca2+-related biomarkers of aging.
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ABSTRACT: Significance: Memory is an essential human cognitive function. Consequently, to unravel the cellular and molecular mechanisms responsible for the synaptic plasticity events underlying memory formation, storage and loss represents a major challenge of present day neuroscience. Recent advances: This review article describes first the wide-ranging functions played by intracellular Ca<sup>2+</sup> signals in the activity-dependent synaptic plasticity processes underlying hippocampal spatial memory, to focus next on how the endoplasmic reticulum Ca<sup>2+</sup> release channels, the ryanodine receptors and the inositol 1,4,5-trisphosphate receptors, contribute to these processes. We present a detailed examination of recent evidence supporting the key role played by Ca<sup>2+</sup> release channels in synaptic plasticity, including structural plasticity, and the formation/consolidation of spatial memory in the hippocampus. Critical issues: Changes in cellular oxidative state affect particularly the function of Ca<sup>2+</sup> release channels and alter hippocampal synaptic plasticity and the associated memory processes. Emphasis is placed in this review on how defective Ca<sup>2+</sup> release, presumably due to increased levels of reactive oxygen species, may cause the hippocampal functional defects associated to aging and Alzheimer's disease. Future directions: Additional studies should examine the precise molecular mechanisms whereby Ca<sup>2+</sup> release channels contribute to hippocampal synaptic plasticity and spatial memory formation/consolidation. Future studies should test if redox-modified Ca2+ release channels contribute to generate the intracellular Ca<sup>2+</sup> signals required for sustained synaptic plasticity and hippocampal spatial memory, and whether loss of redox balance and oxidative stress, by altering Ca<sup>2+</sup> release channel function presumably contribute to the abnormal memory processes that occur during aging and Alzheimer's disease.Antioxidants & Redox Signaling 01/2014; · 8.20 Impact Factor
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ABSTRACT: Introduction: Aging is considered to be one of the most complicated and heterogeneous phenomena and is the main risk factor for most chronic diseases, disabilities and declining health. Aging cells cease to divide and drive the progression of illness through various pathways. Over the years, a number of anti-aging medicines of natural and synthetic origin have been introduced. Indeed, some studies have identified senescent cells as potential therapeutic targets in the treatment of aging and age-related diseases. Areas covered: In this review, the authors highlight and critically review the possible mechanisms of the aging process and related illnesses. The authors give particular attention to illnesses, including Alzheimer's disease, Parkinson's disease, skin aging and cardiovascular diseases. Expert opinion: Several reports have highlighted that mitochondria are a key factor in the progression of aging and neurodegenerative illnesses. This is due to their production of extra amounts of reactive oxygen species, which leads into progressive caspase-dependent apoptosis and cell death. Therefore, strategies to prevent/reduce oxidative stress-mediated aging, whether environmental, nutritional and pharmacological, need to be taken into account. Presently, Drosophila melanogaster and Caenorhabditis elegans, which focus on the evolutionary and genetic foundations of aging, have helped to establish the screening of several synthetic and natural compounds with large cohorts in a quick manner. However, there is yet to be any efficient experimental evidence to prove the exact role of senescent cells in age-related dysfunction and further studies are required to better understand these processes.Expert Opinion on Drug Discovery 02/2014; · 3.47 Impact Factor
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ABSTRACT: Perhaps one of the most remarkable features of T-type calcium channels is their low-threshold of activation that makes these channels important candidates for calcium entry near the resting membrane potential of neurons. Hence, they mediate low-threshold burst discharges that occur during different forms of neuronal rhythmogenesis, but play also important roles in sensory transmission, as well as hormone and neurotransmitter release. Additionally, they have been implicated in an increasing number of neuronal pathologies including neuropathy, autism spectrum disorders and some forms of epilepsy. More recently, an implication of T-type calcium channel in the processing of Amyloid Precursor Protein was documented, with possible implication in the pathogenesis of Alzheimer's disease.Communicative & integrative biology 01/2014; 7(1):e28424.