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Despite extensive research into understanding synaptic mechanisms of striatal plasticity, the functional role played by astrocytes in this region remains to be fully elucidated. It was recently demonstrated that high-frequency stimulation (HFS) of cortical inputs induced long-term depression (LTD) mediated by adenosine A1 receptor (A1R) activation at corticostriatal synapses of the direct pathway [cortico-striatal projection neuron (dSPN)] in the dorsolateral striatum (DLS). Because astrocyte-derived adenosine has been shown to regulate synaptic transmission in several brain areas, we investigated whether this form of neuron-astrocyte signaling contributes to synaptic plasticity in the DLS of male and female mice. We found that cortical HFS increases calcium (Ca 2+ ) levels in striatal astrocytes through activation of metabotropic glutamate receptor type 5 (mGluR5) signaling and that this astrocyte-mediated response is necessary for A1R-mediated LTD. Consistent with this, astrocyte activation with G q designer receptors exclusively activated by designer drugs (DREADDs) induced A1R-mediated synaptic depression at cortico-dSPN synapses. Together, these results indicate that astrocytes are integral elements of striatal A1R-mediated LTD. SIGNIFICANCE STATEMENT Abnormal striatal circuit function is implicated in several disorders such as Parkinson's disease and Huntington's disease. Thus, there is a need to better understand the mechanisms supporting proper striatal activity. While extensive work has revealed the many important contributions from neurons in striatal function, far less is known about the role of astrocytes in this brain area. We show that long-term depression (LTD) at corticostriatal synapses of the direct pathway is not strictly a neuronal phenomenon; astrocytes respond to corticostriatal stimulation and this astrocyte response is necessary for LTD. This research adds to the accumulating evidence that astrocytes are active and integral players in synaptic communication, and that neuron-astrocyte interactions are key cellular processes involved in brain function.

Astrocyte Signaling Gates Long-Term Depression at Corticostriatal Synapses of the Direct Pathway