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

alpha-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 alpha-synucleinopathies. While most studies of alpha-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 alpha-synucleinopathies, i.e., mice expressing high and low levels of the human A53T mutant alpha-synuclein (G2-3 and H5 mice, respectively) globally or selectively in neurons (iSyn mice), mice expressing human wildtype alpha-synuclein (I2-2 mice), and mice expressing A30P mutant alpha-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 alpha-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 alpha-synuclein mutant-specific effects. Moreover, astrocyte Ca2+ hyperexcitability was absent in mice expressing the alpha-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 alpha-synucleinopathies.