Dysfunctions in neuron-glia communications in the aging brain: implications for AD.
We have investigated the properties of the intrinsic astrocyte calcium signal and its physiological consequences on neuronal excitability in hippocampal slices from wildtype mice (WT) and a mice model of Alzheimer Disease (AD; APP/PS1). We found that astrocytes from WT mice at different ages display spontaneous calcium oscillations, which were independent of neuronal electrical activity. Interestingly, the number of oscillating astrocytes were relatively diminished in adult mice at the ages analyzed (5, 12 and 20 months old) when compared with juvenile (15-21 days old) animals, while the mean oscillation frequency remained uniform. In addition to the spontaneous activity, astrocytes showed calcium signaling induced by endogenous neuronal activity in all tested groups. We evaluated the astrocytic calcium responsiveness to different neurotransmitter receptor agonists and we found that astrocytes from young and 5, 12 and 20 months old animals show different calcium responses to the application of ATP, acetylcholine, DHPG (mGluR agonist) and TFLLR (PAR-1R agonist). Indeed, purinergic and cholinergic signaling were preserved in all tested groups, but glutamatergic and thrombin-receptor signaling were diminished during aging. These results suggest an aged-dependent regulation of the spontaneous astrocyte calcium activity as well as the neuron-to-astrocyte communication.
The study of the astrocyte-neuron signaling showed that astrocytes from WT mice at different ages (juvenile, 5, 12 and 20 months) were able to release glutamate and evoke slow inward currents (SICs), which are mediated by NMDA receptor activation. The neuronal recordings of CA1 pyramidal neurons from mice at different ages did not show differences in the mean frequencies of SICs. However, cortical neuronal recordings from APP/PS1 mice (12 months old) showed an increase in the SIC frequency compared with WT, suggesting an enhancement of glutamate release from astrocytes in those mice. These data indicate that astrocyte-to-neuron signaling is conserved during aging with no major changes in their basic properties, but under pathological conditions, such as AD, the astrocyte-to-neuron communication is potentiated boosting the glutamatergic NMDA signaling.
Publications:
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