Dysregulation of astrocytic Ca2+ signaling and gliotransmitter release in mouse models of α-synucleinopathies

Abstract

Abstractα-Synuclein is a major component of Lewy bodies (LB) and Lewy neurites (LN) appearing in the postmortem brain of Parkinson's disease (PD) and other α-synucleinopathies. While most studies of α-synucleinopathies have focused on neuronal and synaptic alterations as well as dysfunctions of the astrocytic homeostatic roles, whether the bidirectional astrocyte–neuronal communication is affected in these diseases remains unknown. We have investigated whether the astrocyte Ca2+ excitability and the glutamatergic gliotransmission underlying astrocyte–neuronal signaling are altered in several transgenic mouse models related to α-synucleinopathies, i.e., mice expressing high and low levels of the human A53T mutant α-synuclein (G2-3 and H5 mice, respectively) globally or selectively in neurons (iSyn mice), mice expressing human wildtype α-synuclein (I2-2 mice), and mice expressing A30P mutant α-synuclein (O2 mice). Combining astrocytic Ca2+ imaging and neuronal electrophysiological recordings in hippocampal slices of these mice, we have found that compared to non-transgenic mice, astrocytes in G2-3 mice at different ages (1–6 months) displayed a Ca2+ hyperexcitability that was independent of neurotransmitter receptor activation, suggesting that the expression of α-synuclein mutant A53T altered the intrinsic properties of astrocytes. Similar dysregulation of the astrocyte Ca2+ signal was present in H5 mice, but not in I2-2 and O2 mice, indicating α-synuclein mutant-specific effects. Moreover, astrocyte Ca2+ hyperexcitability was absent in mice expressing the α-synuclein mutant A53T selectively in neurons, indicating that the effects on astrocytes were cell-autonomous. Consistent with these effects, glutamatergic gliotransmission was enhanced in G2-3 and H5 mice, but was unaffected in I2-2, O2 and iSyn mice. These results indicate a cell-autonomous effect of pathogenic A53T expression in astrocytes that may contribute to the altered neuronal and synaptic function observed in α-synucleinopathies.