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 (Ca2+) 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 Gq 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 A1Rmediated LTD.
Bibliographical noteFunding Information:
This work was supported by the Fondazione Istituto Italiano di Tecnologia (R.T.), the Compagnia di San Paolo Grant 2013 0942 (to R.T.), the Fondazione Cariplo Grant 2013 0871 (to R.T.), the National Institutes of Health (NIH)-National Institute of Neurological Disorders and Stroke (NINDS) Grant R01NS097312 (to A.A.), the NIH-National Institute on Drug Abuse Grant R01DA048822 (to A.A.), and the NIH-NINDS Grant F31NS93751 (to C.D.). We thank Justin Lines for the CALSEE program for Ca21 analysis; Kendrick Kay, Justin Lines, and Mario Martin-Fernandez for MATLAB and CALSEE assistance; Mark Sanders, Guillermo Marques, and Jason Mitchell at the University of Minnesota–University Imaging Centers for assistance using the Leica SP5 Multiphoton Confocal Upright Microscope; Alice Gino and Luca Nava at the Istituto Italiano di Tecnologia for technical assistance during immunohistochemistry and stereotaxic surgery; Ju Chen for generously donating the IP3R2−/− mice; and the University of North Carolina at Chapel Hill Vector Core for providing the DREADDs viruses. Viral vectors used in this study were prepared by the University of Minnesota Viral Vector and Cloning Core. The authors declare no competing financial interests.
- Astrocyte Calcium Signaling
- Long-Term Depression
- Striatal Synaptic Plasticity