Dissecting mechanisms of brain aging by studying the intrinsic excitability of neurons

Rizzo, Valerio; Richman, Jeffrey; Puthanveettil, Sathyanarayanan V.

doi:10.3389/fnagi.2014.00337

Cited by 38 publications

(65 citation statements)

References 109 publications

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“…The analysis of this spontaneous synaptic activity indicates that aged neurons exhibit an increased frequency of [Ca 2+ ]i transients along with decreased spike amplitudes, two indirect signs of hyperexcitability 28,41 . These findings parallel in vivo observations in hippocampal and cortical neurons of clinical and preclinical models of physiopathological aging 29,[42][43][44] .…”

Section: Age-related Functional and Molecular Changes On Cultured Corsupporting

confidence: 83%

Inhibition ofde novoceramide biosynthesis affects aging phenotype in anin vitromodel of neuronal senescence

Granzotto

Bomba

Castelli

et al. 2019

Preprint

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Although aging is considered to be an unavoidable event, recent experimental evidence suggests that the process can be delayed, counteracted, if not completely interrupted. Aging is the primary risk factor for the onset and development of neurodegenerative conditions like Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis. Intracellular calcium (Ca 2+ i) dyshomeostasis, mitochondrial dysfunction, oxidative stress, and lipid dysregulation are critical factors that contribute to senescence-related processes. Ceramides, a class of sphingolipids involved in a wide array of biological functions, are important mediators of cellular senescence, but their role in neuronal aging is still largely unexplored.In this study, we investigated the effects of L-cycloserine (L-CS), an inhibitor of de novo ceramide biosynthesis, on the aging phenotype of cortical neurons that have been maintained in culture for 22 days, a setting employed as an in vitro model of cellular senescence. Our findings indicate that 'aged' neurons display, when compared to control cultures, overt dysregulation of cytosolic and subcellular [Ca 2+ ]i levels, mitochondrial dysfunction, increased reactive oxygen species generation, altered synaptic activity as well as the activation of neuronal death-related molecules. Treatment with L-CS (30 µM) positively affected the senescent phenotype, a result accompanied by recovery of neuronal [Ca 2+ ]i signaling, and reduction of mitochondrial dysfunction and reactive oxygen species generation.The results suggest that the de novo ceramide biosynthesis may represent a critical intermediate in the molecular and functional cascade leading to neuronal senescence. Our findings also identify ceramide biosynthesis inhibitors as promising pharmacological tools to decrease agerelated neuronal dysfunctions. L-CS treatment does not modify NCX activityCeramides can modulate the activity of the plasmalemmal Na + -Ca 2+ exchanger (NCX) 25 , a low capacitance high-affinity system that critically regulates cellular [Ca 2+ ]i. We, therefore, investigated

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Section: Age-related Functional and Molecular Changes On Cultured Corsupporting

confidence: 83%

Inhibition ofde novoceramide biosynthesis affects aging phenotype in anin vitromodel of neuronal senescence

Granzotto

Bomba

Castelli

et al. 2019

Preprint

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“…Cortical inputs to the claustrum are organized in a topographic manner along the anterior-posterior axis [2,4,19,44]. We therefore next examined differences in the distribution of labelled claustrum neurons along this axis.…”

Section: Location Of Claustrum Cells That Project To the Accmentioning

confidence: 99%

“…Because intrinsic neuronal properties change with age [44], we determined whether the parameters used for cell classification changed during development. For this purpose, our data were divided into two age groups: 5-6-week-old and 7-11-week-old mice.…”

Section: Four Claustrum Cell Types Project To the Accmentioning

confidence: 99%

Functional properties, topological organization and sexual dimorphism of claustrum neurons projecting to anterior cingulate cortex

2017

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Objective: To define the physiological properties of neurons projecting from the claustrum to the anterior cingulate cortex (ACC). Design: To identify the claustrum in live slices, we used a transgenic mouse line that expresses yellow fluorescent protein (YFP)-tagged Volvox channelrhodopsin-1 at high levels within the claustrum. Claustrum cells projecting to the ACC were identified by retrograde labelling. Whole-cell patch-clamp recordings from labelled claustrum neurons were used to characterize the intrinsic electrical properties of these neurons. Cells were classified according to their intrinsic electrical properties, based on a previous classification scheme. Results: Labelled neurons were found in the claustrum but not the insular cortex. Four types of ACC-projecting neurons were identified based on action potential adaptation and waveform: strongly adapting (SA) cell types 2, 3 and 4, and moderately adapting (MA) cell type 2. Labelled cells were predominantly SA4 in the anterior (44%) and posterior (63%) claustrum, while MA2 predominated (77%) in the central claustrum. The male anterior claustrum showed a bias toward SA3 cells (53%) while the female anterior claustrum showed a bias toward SA3 cells (76%). Conclusions: There is ipsilateral dominance for ACC-projecting claustrum neurons, with the intrinsic properties of these neurons varying along the anterior-posterior axis. Sexual dimorphism was observed in ACC-projecting claustrum cells. Our results are consistent with the hypothesis that the claustrum serves as a link between the insular cortex and the ACC. ARTICLE HISTORY

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“…The generation of slow waves during sleep, which is associated with the dissipation of sleep need, is reduced in aging (15). Likewise, cortical excitability (16), a basic aspect of brain function implicated in age-related cognitive decline (17, 18), shows less variations during prolonged wakefulness. Age-related alterations in the regulation of sleep and wakefulness are not only associated with current cognition (19, 20), but also predicts future cognitive trajectories, including the risk of developing dementia (12, 21–23).…”

Section: Introductionmentioning

confidence: 99%

Preserved wake-dependent cortical excitability dynamics predict cognitive fitness beyond age-related brain alterations

Egroo

Narbutas

Chylinski

et al. 2019

Preprint

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1Age-related cognitive decline is rooted in alterations in brain integrity as well as in sleep-wake 2 regulation. Here, we investigated whether preserved sleep-wake regulation of cortical function 3 during wakefulness could represent a positive factor for cognitive fitness in aging, independently 4 of early age-related alterations in brain structure associated with Alzheimer's disease 5 neuropathology. We quantified slow waves generation during sleep and cortical excitability 6 dynamics during prolonged wakefulness as sensitive markers of age-related alteration in sleep-7 wake regulation in 60 healthy late middle-aged individuals (50-69y; 42 women). We evaluated 8 brain integrity with amyloid-beta-PET and tau-PET, and with MRI. Participants' cognition was 9 extensively assessed. We first confirm that sleep slow waves generation is associated with 10 amyloid-beta burden. Although cortical excitability dynamics during wakefulness is related to 11 sleep slow waves, it is not associated with amyloid-beta nor with tau burden. We further show that 12 individuals with preserved cortical excitability dynamics showed better cognitive performance, 13 particularly in the executive domain, which is crucial for successful cognitive aging. Critically, 14 this association remained significant after accounting for brain integrity measures. Preserved 15 dynamics of basic brain function during wakefulness could be essential to cognitive fitness in 16 aging, independently from age-related brain structural deteriorations that can ultimately lead to 17 dementia. 18 19

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Dissecting mechanisms of brain aging by studying the intrinsic excitability of neurons

Cited by 38 publications

References 109 publications

Inhibition ofde novoceramide biosynthesis affects aging phenotype in anin vitromodel of neuronal senescence

Inhibition ofde novoceramide biosynthesis affects aging phenotype in anin vitromodel of neuronal senescence

Functional properties, topological organization and sexual dimorphism of claustrum neurons projecting to anterior cingulate cortex

Preserved wake-dependent cortical excitability dynamics predict cognitive fitness beyond age-related brain alterations

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