Investigation of age-related cognitive decline using mice as a model system: neurophysiological correlates (original) (raw)
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Neuroscience Letters, 2007
Aging is associated with increased vulnerability to neurodegenerative conditions such as Parkinson's and Alzheimer's disease and greater neuronal deficits after stroke and epilepsy. Emerging studies have implicated increased levels of intracellular calcium ([Ca 2+ ] i ) for the neuronal loss associated with aging related disorders. Recent evidence demonstrates increased expression of voltage gated Ca 2+ channel proteins and associated Ca 2+ currents with aging. However, a direct comparison of [Ca 2+ ] i levels and Ca 2+ homeostatic mechanisms in hippocampal neurons acutely isolated from young and mid-age adult animals has not been performed. In this study, Fura-2 was used to determine [Ca 2+ ] i levels in CA1 hippocampal neurons acutely isolated from young (4-5 months) and mid-age (12-16 months) Sprague-Dawley rats. Our data provide the first direct demonstration that mid-age neurons in comparison to young neurons manifest significant elevations in basal [Ca 2+ ] i levels. Upon glutamate stimulation and a subsequent [Ca 2+ ] i load, mid-age neurons took longer to remove the excess [Ca 2+ ] i in comparison to young neurons, providing direct evidence that altered Ca 2+ homeostasis may be present in animals at significantly younger ages than those that are commonly considered aged (≥ 24 months). These alterations in Ca 2+ dynamics may render aging neurons more vulnerable to neuronal death following stroke, seizures or head trauma. Elucidating the functionality of Ca 2+ homeostatic mechanisms may offer an understanding of the increased neuronal loss that
Increased phosphorylation of the neuronal L-type Ca 2+ channel Ca v 1.2 during aging
Proceedings of the National Academy of Sciences, 2003
An increase in Ca 2+ influx through L-type Ca 2+ channels is thought to contribute to neuronal dysfunctions that underlie senile symptoms and Alzheimer's disease. The molecular basis of the age-dependent up-regulation in neuronal L-type Ca 2+ channel activity is largely unknown. We show that phosphorylation of the L-type channel Ca v 1.2 by cAMP-dependent protein kinase is increased >2-fold in the hippocampus of aged rats. The hippocampus is critical for learning and is one of the first brain regions to be affected in Alzheimer's disease. Phosphorylation of Ca v 1.2 by cAMP-dependent protein kinase strongly enhances its activity. Therefore, increased Ca v 1.2 phosphorylation may account for a substantial portion of the age-related rise in neuronal Ca 2+ influx and its neuropathological consequences.
Neuroscience Letters, 1994
Aged, memory-impaired rats do not learn an 8-arm radial maze task but differ in their performance along testing. The aim of this study was to determine whether any of the systems that govern calcium homeostasis in synaptosomes may be related to that difference in performance. A negative correlation between initial (5 s) K+-stimulated 45Ca2+ uptake and the behavioral scores from the last testing sessions was obtained. K+-stimulated 45Ca2+ uptake showed also a negative correlation with an improvement score that evaluates the progress made by the rat along testing. The results support the notion that calcium inflow through synaptosomal voltage gated calcium channels in old rats is inversely correlated with their behavior. This may explain the beneficial effects of organic calcium channel blockers on behavioral performance in aged animals.
Altered Calcium Metabolism in Aging CA1 Hippocampal Pyramidal Neurons
Journal of Neuroscience, 2013
Altered neuronal calcium homeostasis is widely hypothesized to underlie cognitive deficits in normal aging subjects, but the mechanisms that underlie this change are unknown, possibly due to a paucity of direct measurements from aging neurons. Using CCD and two-photon calcium imaging techniques on CA1 pyramidal neurons from young and aged rats, we show that calcium influx across the plasma membrane increases with aging, and that this change is countered by increased intracellular calcium buffering. The additional buffer in aging neurons balances the increased calcium influx following a small number (Ͻ3) action potentials, but is overwhelmed during sustained or theta-like activity which leads to a greater rise in intracellular calcium concentration in aging than that in young neurons. Our results demonstrate that calcium overload occurs regularly in aging CA1 pyramidal neurons under physiological conditions. This overload may be a critical factor in age-related decline in hippocampus-dependent cognitive function.
Parameters of calcium homeostasis in normal neuronal ageing
Journal of Anatomy, 2000
The last decade has witnessed a significant turn in our understanding of the mechanisms responsible for the decline of cognitive functions in aged brain. As has been demonstrated by detailed morphological reassessments, the senescence-related changes in cognition cannot be attributed to a simple decrease in the number of neurons. It is becoming clearer that a major cause of age-induced deterioration of brain capability involves much subtler changes at the level of synapses. These changes are either morphological, i.e. reduction in the number of effective synapses and\or functional alterations, i.e. changes in the efficacy of remaining synapses. Important questions are now raised regarding the mechanisms which mediate these synaptic changes. Clearly, an important candidate is calcium, the cytotoxic role of which is already firmly established. The wealth of evidence collected so far regarding the changes of Ca# + homeostasis in aged neurons shows that the overall duration of cytoplasmic Ca# + signals becomes longer. This is the most consistent result, demonstrated on different preparations and using different techniques. What is not yet clear is the underlying mechanism, as this result could be explained either through an increased Ca# + influx or because of a deficit in the Ca# + buffering\clearance systems. It is conceivable that these prolonged Ca# + signals may exert a local excitotoxic effect, removing preferentially the most active synapses. Uncovering of the role of Ca# + in the synaptic function of the aged brain presents an exciting challenge for all those involved in the neurobiology of the senescent CNS.
Age-related loss of calcium binding proteins in rabbit hippocampus
Neurobiology of Aging, 1996
Age-related loss of calcium binding proteins in rabbit hippocampus. NEUROBIOL AGING 17(3) 459-465, 1996.-Using immunocytochemistry hippocampal levels of the calcium binding proteins calbindin 28K (CB) and parvalbumin (PV) was studied in young (1 month) to very old (60 month) Albino rabbits. Young (3 month) and senescent (30 month) Wistar rats were also examined to compare the distribution and age dependency of PV and CB in both species. The distribution of PV-ir is similar in the rabbit and rat hippocampus. Aging in both species yielded a small loss of PV-ir in axon terminals. The presence of CB-ir interneurons throughout the hippocampus, and the heavy investment of the dentate gyrus (DG) granular cells with CB-ir was also similar in both species. In rabbits, the number of CB-ir interneurons in the CA1, as well as the density of CB-ir in the DG decreased in the first year of life, and did not change between 12-48 months of age. A secondary reduction in the density of CB-ir in the DG was observed at ages beyond 48 months. A similar loss of CB-ir in the DG occurred in the rat. In the CA1, however, the density of CB-ir was similar in young and aged rats. Another remarkable finding was the total absence of CB-ir in CA1 pyramidal neurons of rabbits at any age. Thus, the distribution and age dependency of PV-ir in the hippoc~unpus is similar in both species. The decline of CB-ir in the DG with advancing age is very prominent and may be related to an altered calcium homeostasis in these cells. However, the absence of CB-ir in the CA1 of rabbits makes a causal role for CB in the functional decline of CA1 pyramidal cells during aging unlikely. Calbindin 28K Parvalbumin Immunocytochemistry Aging Hippocampus Rabbit Rat
Calcium-dependent afterhyperpolarization and learning in young and aging hippocampus
Life Sciences, 1996
Hippocampally-dependent trace eyeblink conditioning has been shown to be affected by aging. Aging animals take more trials to acquire the association and are more likely to be unable to learn the task. Hippocampal neurons show decreased post-burst afterhyperpolarizations (AHPs) and less accomodation after conditioning, in a time-dependent fashion which may relate to the role of hippocampus in learning consolidation.
Calcium chelation improves spatial learning and synaptic plasticity in aged rats
Experimental Neurology, 2006
Impaired regulation of intracellular calcium is thought to adversely affect synaptic plasticity and cognition in the aged brain. Comparing young (2-3 months) and aged (23-26 months) Fisher 344 rats, stratum radiatum-evoked CA1 field EPSPs were smaller and long-term potentiation (LTP) was diminished in aged hippocampal slices. Resting calcium, in presynaptic axonal terminals in the CA1 stratum radiatum area, was elevated in aged slices. Loading the slice with the calcium chelator, BAPTA-AM, depressed LTP in young slices, but enhanced this plasticity in old slices. Forty-five minutes following LTP-inducing high frequency stimulation, resting calcium levels were significantly increased in both young and old presynaptic terminals, and significantly reduced by pretreatment with BAPTA-AM. In vivo, intraperitoneal administration of BAPTA-AM prior to training in the reference memory version of the Morris water maze test, significantly improved the acquisition of spatial learning in aged animals, without a significant effect in young rats. These results support the hypothesis that increasing intracellular neuronal buffering power for calcium in aged rats ameliorates age-related impaired synaptic plasticity and learning.
Remodeling of Intracellular Ca2+ Homeostasis in Rat Hippocampal Neurons Aged In Vitro
International Journal of Molecular Sciences, 2020
Aging is often associated with a cognitive decline and a susceptibility to neuronal damage. It is also the most important risk factor for neurodegenerative disorders, particularly Alzheimer’s disease (AD). AD is related to an excess of neurotoxic oligomers of amyloid β peptide (Aβo); however, the molecular mechanisms are still highly controversial. Intracellular Ca2+ homeostasis plays an important role in the control of neuronal activity, including neurotransmitter release, synaptic plasticity, and memory storage, as well as neuron cell death. Recent evidence indicates that long-term cultures of rat hippocampal neurons, resembling aged neurons, undergo cell death after treatment with Aβo, whereas short-term cultures, resembling young neurons, do not. These in vitro changes are associated with the remodeling of intracellular Ca2+ homeostasis with aging, thus providing a simplistic model for investigating Ca2+ remodeling in aging. In vitro aged neurons show increased resting cytosolic...