Astrocyte 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 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.

Astrocytic processes: from tripartite synapses to the active milieu

“…According to the paradigm of the active milieu, neuronal activity and synaptic signaling reciprocally interact with surrounding elements. Changes in the leaflet SVR may occur under both physiological and pathological conditions that are associated with active milieu remodeling [13,25,[64][65][66] and result in multiple changes in astrocyte Ca 2+ and Na + dynamics, diffusion pathways of the ECS, glutamate uptake, and K + clearance. In particular, rapid SVR changes [94].…”

Astroglia in ageing

“…2). More detailed analysis of volume fraction of optically unresolved portions of the cell also revealed significant decrease in peripheral processes indicating reduced astroglial synaptic coverage in the old brain [49]. It is also a weak partial agonist at human and mouse P2X4 receptors, but an antagonist at the rat P2X4 receptor; it has little or no effect at other P2X and P2Y receptors), at holding potential of -80 mV.…”

“…Ageing is not associated with substantial changes in membrane physiology. Neither resting membrane potential nor membrane input resistance of cortical astrocytes change with ageing [49,50]. Astrocytes from old humans and rodents express functional receptors to neurotransmitters and generate Ca 2+ signals in response to appropriate stimulation [50][51][52]; parameters of these signals do not differ much from those observed in young or adult animals.…”

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

“…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 ).…”

“…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.…”