Astrocytes dystrophy in ageing brain parallels impaired synaptic plasticity

Abstract

Little is known about age-dependent changes in structure and function of astrocytes and of the impact of these into the cognitive decline in the senescent brain. The prevalent view on 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 reorganization 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 astroglial mechanisms of age-dependent decline in learning and memory.

Physiological and Pathological Ageing of Astrocytes in the Human Brain

“…In conclusion, there are multiple indications that astrocyte homeostatic functions are altered in the aged human brain, which is in corroboration with rodent studies [74][75][76]. These homeostatic changes could go hand in hand with an increase in the inflammatory function of astrocytes, which is discussed below.…”

Astroglial asthenia and loss of function, rather than reactivity, contribute to the ageing of the brain

“…Finally, the morphology of astrocytes in brain slices from mice of different ages (3, 9 and 24 months) was visualised using intercellular perfusion with low molecular weight fluorescent probe Alexa Fluor 594 [152]. This fluorescent probe diffuses through the cytosol and penetrates in the most distant parts of the cell labelling even tiny perisynaptic processes.…”

“…This approach presumes that fluorescence measured from the soma reflects 100% of astrocyte space occupancy, whereas the fluorescence of unresolved area is proportional to the volume fraction of optically irresolvable astrocyte processes in any given area [114]. It turned out that the volume fraction occupied by peripheral processes diminishes with age, thus indicating decreased astroglial synaptic coverage in the old brain [152]. Astroglial peripheral processes are one of the main contributors to the neuropil [194], and their shrinkage is associated with an increase in diffusion channels and hence to an increase in mean diffusivity of the grey matter (Fig.…”

Modulation of Glial Function in Health, Aging, and Neurodegenerative Disease

“…Astrocytes in aged mice also mirror aged microglia in that they undergo region-specific morphological changes, demonstrating variable changes in cell complexity, a reduced domain size with short, stubby processes, and decreased astrocyte coupling through gap junctions (Rodríguez et al, 2014;Jyothi et al, 2015;Bondi et al, 2021;Popov et al, 2021). Age-dependent morphological changes were also concomitant with deficiencies in astrocytic physiology, specifically in potassium buffering and glutamate clearance, which impaired synaptic plasticity and hippocampal long-term potentiation (Popov et al, 2021). Taken together, these findings suggest that changes in microglia and astrocyte function due to aging may alter outcomes following brain injury or impact age-associated disease progression, though this continues to be a topic of debate.…”

“…Similar to microglia, cultured astrocytes isolated from aged mice display an increase in mitochondrial activity, which limits the substrate supply from astrocytes to neurons and can contribute to age-related cognitive decline (Jiang and Cadenas, 2014). Astrocytes in aged mice also mirror aged microglia in that they undergo region-specific morphological changes, demonstrating variable changes in cell complexity, a reduced domain size with short, stubby processes, and decreased astrocyte coupling through gap junctions (Rodríguez et al, 2014;Jyothi et al, 2015;Bondi et al, 2021;Popov et al, 2021). Age-dependent morphological changes were also concomitant with deficiencies in astrocytic physiology, specifically in potassium buffering and glutamate clearance, which impaired synaptic plasticity and hippocampal long-term potentiation (Popov et al, 2021).…”