Astrocyte dystrophy in ageing brain parallels impaired synaptic plasticity

Little is known about age‐dependent changes in structure and function of astrocytes and of the impact of these on the cognitive decline in the senescent brain. The prevalent view on the age‐dependent increase in reactive astrogliosis and astrocytic hypertrophy requires scrutiny and detailed analysis. Using two‐photon microscopy in conjunction with 3D reconstruction, Sholl and volume fraction analysis, we demonstrate a significant reduction in the number and the length of astrocytic processes, in astrocytic territorial domains and in astrocyte‐to‐astrocyte coupling in the aged brain. Probing physiology of astrocytes with patch clamp, and Ca2+ imaging revealed deficits in K+ and glutamate clearance and spatiotemporal reorganisation of Ca2+ events in old astrocytes. These changes paralleled impaired synaptic long‐term potentiation (LTP) in hippocampal CA1 in old mice. Our findings may explain the astroglial mechanisms of age‐dependent decline in learning and memory.

• Publication year

  2021

• Venue

  Aging Cell

• Publication date

  2021-03-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1111/acel.13334PMID 33675569PMCID 7963330
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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  2020cited by this paper
• Reversal of calcium dysregulation as potential approach for treating Alzheimer's Disease.

  2020cited by this paper
• Concomitant

  2020cited by this paper
• Spatiotemporal pattern of calcium activity in astrocytic network.

  2019influential reference
• Astroglial atrophy in Alzheimer’s disease

  2019cited by this paper
• Na+-dependent transporters: The backbone of astroglial homeostatic function.

  2019cited by this paper
• Control of Long-Term Plasticity by Glutamate Transporters

  2019cited by this paper
• Astrocytes and Aging

  2018cited by this paper
• Astrocytic Atrophy Following Status Epilepticus Parallels Reduced Ca2+ Activity and Impaired Synaptic Plasticity in the Rat Hippocampus

  2018influential reference
• Diversity of Astroglial Effects on Aging- and Experience-Related Cortical Metaplasticity

  2018cited by this paper
• Activity-dependent changes in transporter and potassium currents in hippocampal astrocytes.

  2018cited by this paper
• Physiology of Astroglia.

  2018cited by this paper
• Morphological profile determines the frequency of spontaneous calcium events in astrocytic processes

  2018cited by this paper
• Astrocytic Coverage of Dendritic Spines, Dendritic Shafts, and Axonal Boutons in Hippocampal Neuropil

  2018cited by this paper
• Neuron–astrocyte signaling is preserved in the aging brain

  2017cited by this paper
• Glial cell morphological and density changes through the lifespan of rhesus macaques.

  2016cited by this paper
• Astrocytes in physiological aging and Alzheimer's disease.

  2016cited by this paper
• Astrocyte sodium signaling and the regulation of neurotransmission

  2016cited by this paper
• Regional age differences in gray matter diffusivity among healthy older adults

  2016cited by this paper
• Impairments of neural circuit function in Alzheimer's disease

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• Glial Asthenia and Functional Paralysis

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• Astroglial potassium clearance contributes to short‐term plasticity of synaptically evoked currents at the tripartite synapse

  2014cited by this paper
• Glia selectively approach synapses on thin dendritic spines

  2014cited by this paper
• Astroglial cradle in the life of the synapse

  2014influential reference
• Spatiotemporal calcium dynamics in single astrocytes and its modulation by neuronal activity.

  2014cited by this paper
• Complex and region-specific changes in astroglial markers in the aging brain.

  2014cited by this paper
• Astrocytic Ca2+ signals are required for the functional integrity of tripartite synapses

  2013cited by this paper
• Calcium-induced outgrowth of astrocytic peripheral processes requires actin binding by Profilin-1.

  2013cited by this paper
• Review: Microglia of the aged brain: primed to be activated and resistant to regulation

  2013cited by this paper
• Subcellular location of astrocytic calcium stores favors extrasynaptic neuron-astrocyte communication.

  2013cited by this paper
• Effect of age on neocortical brain cells in 90+ year old human females--a cell counting study.

  2013cited by this paper
• Retrograde synaptic signaling mediated by K+ efflux through postsynaptic NMDA receptors.

  2013cited by this paper
• The Neuron-Astrocyte-Microglia Triad in Normal Brain Ageing and in a Model of Neuroinflammation in the Rat Hippocampus

  2012cited by this paper
• Astroglial excitability and gliotransmission: an appraisal of Ca2+ as a signalling route

  2012cited by this paper
• Sequence variants of interleukin 6 (IL-6) are significantly associated with a decreased risk of late-onset Alzheimer's disease

  2012cited by this paper
• Age‐dependent remodelling of ionotropic signalling in cortical astroglia

  2011cited by this paper
• The impact of glial activation in the aging brain.

  2010cited by this paper
• Impaired glial glutamate uptake induces extrasynaptic glutamate spillover in the spinal sensory synapses of neuropathic rats.

  2010cited by this paper
• Concomitant astroglial atrophy and astrogliosis in a triple transgenic animal model of Alzheimer's disease

  2010cited by this paper
• Electrophysiological properties and gap junction coupling of striatal astrocytes.

  2008cited by this paper
• Gene expression changes in the course of normal brain aging are sexually dimorphic

  2008cited by this paper
• Neocortical glial cell numbers in human brains.

  2008cited by this paper
• Age-related changes of astorocytes, oligodendrocytes and microglia in the mouse hippocampal CA1 sector.

  2007cited by this paper
• Inflammaging as a major characteristic of old people: can it be prevented or cured?

  2007cited by this paper
• The importance of being subtle: small changes in calcium homeostasis control cognitive decline in normal aging

  2007cited by this paper
• The Pathogenesis of Alzheimers Disease—Is It a Lifelong “Calciumopathy”?

  2007cited by this paper
• Redefining the concept of reactive astrocytes as cells that remain within their unique domains upon reaction to injury

  2006cited by this paper
• Microglia in the Aging Brain

  2006cited by this paper
• Calcium Dynamics in Cortical Astrocytes and Arterioles During Neurovascular Coupling

  2004cited by this paper
• Ca2+ regulation and gene expression in normal brain aging.

  2004cited by this paper
• Image analysis of GFA-positive astrocytes from adolescence to senescence

  2004cited by this paper
• Plasticity and Neuroplasticity

  2004cited by this paper
• NR2B-Containing Receptors Mediate Cross Talk among Hippocampal Synapses

  2004cited by this paper
• A Scheme for Coherence-Enhancing Diffusion Filtering with Optimized Rotation Invariance

  2002cited by this paper
• Control of Glutamate Clearance and Synaptic Efficacy by Glial Coverage of Neurons

  2001cited by this paper
• Plasticity and neuroplasticity.

  2000cited by this paper
• NEUROwords 8 Plasticity and Neuroplasticity

  2000cited by this paper
• Gender effects on age-related changes in brain structure.

  2000cited by this paper
• Calcium and neuronal ageing.

  1998cited by this paper
• Glial reaction in aging and Alzheimer's disease

  1998cited by this paper
• Glial reaction in the hippocampal formation is highly correlated with aging in human brain.

  1997cited by this paper
• Increases of glial fibrillary acidic protein in the aging female mouse brain.

  1995cited by this paper
• GFAP mRNA increases with age in rat and human brain.

  1993cited by this paper
• Age-related changes in glial fibrillary acidic protein mRNA in the mouse brain.

  1991cited by this paper
• Hypothesis on the regulation of cytosol calcium concentration and the aging brain.

  1987cited by this paper
• The Principles of Psychology

  year unknowncited by this paper

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  2026cites this paper
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  2025cites this paper
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  2024cites this paper
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  2024cites this paper
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  2024cites this paper
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  2024cites this paper
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  2023cites this paper
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  2023cites this paper
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  2023cites this paper
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  2023cites this paper
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  2023cites this paper
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  2023cites this paper
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  2023cites this paper
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  2023cites this paper
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  2023cites this paper
• CNS Ageing in Health and Neurodegenerative Disorders

  2023cites this paper
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  2023cites this paper
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  2023influential citation
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  2023cites this paper
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  2023cites this paper
• Astrocytes in Ageing.

  2023cites this paper
• The Brain and Spinal Microvasculature in Normal Aging.

  2023cites this paper
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  2023influential citation
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  2023cites this paper
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  2023cites this paper
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  2023cites this paper
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  2023cites this paper