Optogenetic stimulation of nigral astrocytes is neuroprotective in a 6-OHDA model of neurodegeneration.
Parkinson disease is characterized by the loss of dopaminergic neurons in the substantia nigra. Glial-glial crosstalk is essential for maintaining the regional milieu and appears to be particularly important in modulating neuroinflammation and many aspects of neurodegeneration. In particular, astrocytes are critical for maintaining dopamine neuronal integrity and survival, and astroglial dysfunction is prominent in Parkinson disease. As such, astrocytes represent a potentially critical therapeutic target in neurodegeneration. In this study, in vivo optogenetics were used to selectively stimulate astrocytes in the substantia nigra following a striatal 6-OHDA lesion. Remarkably, a single bout of optogenetic stimulation was sufficient to attenuate motor deficits and dopamine neuron loss induced by the neurotoxin. Furthermore, bulk RNAseq and snRNAseq analysis of the substantia nigra revealed extensive changes in both microglia and oligodendrocytes, suggesting that the neuroprotective effects of stimulating astrocytes may be mediated through alterations in glia-glia crosstalk. Altogether, this work demonstrates the importance of understanding glia-glia interactions in neurodegeneration.