IMPAIRED ENDOCANNABINOID NEURON-ASTROCYTE SIGNALING IN A MOUSE MODEL OF PARKINSON’S DISEASE

Astrocytes actively modulate neuronal communication by the release of neuroactive substances termed gliotransmitters. This bidirectional signaling between neurons and astrocytes is necessary for proper brain functioning and its dysfunction can contribute to disease states. In the dorsolateral striatum (DLS), D1- and D2-medium spiny neurons (MSNs) and astrocytes show a type of bidirectional communication mediated by endocannabinoids (eCBs) that results in the synaptic potentiation of a heteroneuronal synapse, known as heteroneuronal eCB-mediated synaptic potentiation (eSP). Yet the potential dysregulation of this neuron-astrocyte signaling and its contribution to pathological conditions remains largely unexplored. Combining astrocytic Ca²⁺-imaging and neuronal whole-cell patch clamp electrophysiological recordings in striatal slices, we found that eCB-mediated communication between MSNs and astrocytes in the DLS is impaired in a mouse model of Parkinson’s disease. Upon neuronal depolarization of MSNs, astrocytes of saline-injected mice showed an increase in intracellular Ca²⁺ levels, which triggered the release of glutamate, causing heteroneuronal eSP. However, in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice, neuronal depolarization did not induce an increase in Ca²⁺ levels in astrocytes, and heteroneuronal eSP was consequently lost. Interestingly, in MSNs of MPTP-treated mice, depolarization-induced suppression of excitation (DSE) remained unaffected. Furthermore, direct stimulation of astrocytes with ATP was able to restore the heteroneuronal eSP lost in these mice, pointing to a specific impairment in MSN-astrocyte communication. These results underscore the potential contribution of impaired eCB-mediated neuron-astrocyte signaling to the pathophysiology of Parkinson’s disease and suggest that alterations in neuron-astrocyte communication may play an important role in different neurodegenerative diseases.