Neuron–astrocyte signaling is preserved in the aging brain

Abstract

Astrocytes play crucial roles in brain homeostasis and are emerging as regulatory elements of neuronal and synaptic physiology by responding to neurotransmitters with Ca2+ elevations and releasing gliotransmitters that activate neuronal receptors. Ageing involves neuronal and astrocytic alterations, being considered risk factor for neurodegenerative diseases. Most evidence of the astrocyte-neuron signaling is derived from studies with young animals; however, the features of astrocyte-neuron signaling in adult and aging brain remain largely unknown. We have investigated the existence and properties of astrocyte-neuron signaling in physiologically and pathologically ageing mouse hippocampal and cortical slices at different lifetime points (0.5 to 20 month-old animals). We found that astrocytes preserved their ability to express spontaneous and neurotransmitter-dependent intracellular Ca2+ signals from juvenile to ageing brains. Likewise, resting levels of gliotransmission, assessed by neuronal NMDAR activation by glutamate released from astrocytes, were largely preserved with similar properties in all tested age-groups, but DHPG-induced gliotransmission was reduced in aged mice. In contrast, gliotransmission was enhanced in the APP/PS1 mouse model of Alzheimer’s disease, indicating a dysregulation of astrocyte-neuron signaling in pathological conditions. Disruption of the astrocytic IP3R2 mediated-signaling, which is required for neurotransmitter-induced astrocyte Ca2+ signals and gliotransmission, boosted the progression of amyloid plaque deposits and synaptic plasticity impairments in APP/PS1 mice at early stages of the disease. Therefore, astrocyte-neuron interaction is a fundamental signaling, largely conserved in the adult and ageing brain of healthy animals, but it is altered in Alzheimer’s disease, suggesting that dysfunctions of astrocyte Ca2+ physiology may contribute to this neurodegenerative disease.

The APPswe/PS1A246E mutations in an astrocytic cell line leads to increased vulnerability to oxygen and glucose deprivation, Ca2+ dysregulation, and mitochondrial abnormalities

“…These results are of particular interest as Ca 2+ signaling in astrocytes has been postulated to contribute to the progression of AD (Gomez‐Gonzalo et al . ). Excessive Ca 2+ responses are known to lead to apoptotic and necrotic cell death, which is demonstrated by the fact that thapsigargin induced Ca 2+ cell death in APPswe/PS1A246E cell line but not in the control (Fig.…”

Astrocyte dysfunction in Alzheimer disease

“…This, in turn, activates neuronal NMDA receptors and leads to synaptic loss (Talantova et al, 2015). In addition, astrocytic mGluRs evoked increased hippocampal and cortical SIC frequency in AD mouse models, indicative of enhanced glutamatergic gliotransmission and, therefore, of dysregulated astrocyte-neuron signaling (Gomez-Gonzalo et al, 2017). Amyloid-dependent glutamate release sufficient to promote neuronal death has also been attributed to egress through connexin hemichannels (Orellana et al, 2011).…”

Astrocytes dystrophy in ageing brain parallels impaired synaptic plasticity

“…The main biophysical properties of the plasmalemma seem to change very little; the resting membrane potential and input membrane resistance do not differ between young and old rodents (Lalo et al, 2011). Astrocytes from old animals generate membrane currents and Ca 2+ responses to major neurotransmitters, indicative of expression of ionotropic glutamate and P2X receptors as well as metabotropic glutamate, noradrenaline, cannabinoid and P2Y receptors (Gomez-Gonzalo et al, 2017;Lalo et al, 2018;Lalo et al, 2011). Similarly, astrocytes seem to maintain functional glutamate transporters (Lalo et al, 2011) responsible for glutamate clearance.…”